Conference Coverage

In the treatment of patients with newly diagnosed multiple myeloma (MM) who are not eligible for stem cell transplant or are transplant-deferred, adding subcutaneous daratumumab to bortezomib/lenalidomide/dexamethasone (D-VRd) significantly improves minimal residual disease (MRD) outcomes among patients, the first results from the phase 3 CEPHEUS trial showed.

“CEPHEUS is the first phase 3 daratumumab trial with a primary endpoint of MRD negativity,” said first author Saad Z. Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York City, in presenting late-breaking findings at the annual meeting of the International Myeloma Society in Rio de Janeiro, Brazil in late September.

“We found that adding daratumumab to VRd significantly improved depth and duration of response,” Dr. Usmani said. “[The quadruplet regimen] has the potential to improve clinical outcomes for transplant-ineligible or transplant-deferred patients with newly diagnosed MM who can tolerate bortezomib.”

For newly diagnosed patients with MM who are not eligible for a stem cell transplant, the triplet MAIA regimen of daratumumab, lenalidomide, and dexamethasone is a recommended standard of care, having shown a median overall survival of 7.5 years.

However, for those who are transplant eligible, the PERSEUS regimen of D-VRd followed by daratumumab/lenalidomide maintenance, has shown significant progress-free survival benefits compared with the standard of care.

For the ongoing, multicenter, open-label CEPHEUS study, Dr. Usmani and his colleagues investigated the efficacy of the quadruplet D-VRd regimen compared with VRd alone among newly diagnosed patients who are transplant-ineligible or deferred (not planned as initial therapy).

In the trial, 395 adult patients with transplant-ineligible or transplant-deferred newly diagnosed MM all were initially treated with eight 21-day cycles of VRd, followed by 28-day cycles of lenalidomide until disease progression.

The patients were then randomized to VRd either with (n = 197) or without (n = 198) subcutaneous daratumumab.

Those receiving daratumumab received the subcutaneous therapy weekly in cycles 1 and 2, every 3 weeks in cycles 3-8, and every 4 weeks in cycles 9 or more, until disease progression.

The patients had a median age of 70 years; 28.1% had International Staging System stage III disease, and 13.2% had high-risk cytogenetics.

For the primary endpoint, with a median follow-up of 58.7 months, those in the daratumumab group had a significantly higher rate of being MRD-negative (60.9%) than the VRd-only group (39.4%; odds ratio [OR], 2.37; P < .0001).

Likewise, progression-free survival (PFS) was significantly improved with the daratumumab regimen vs VRd (hazard ratio [HR], 0.57; P = .0005).

A median PFS was not reached for daratumumab plus VRd, compared with 52.6 months for the VRd group, while estimated 54-month PFS rates were 68.1% vs 49.5%, respectively.

A complete response or better was achieved among 81.2% in the daratumumab regimen vs 61.6% with VRd alone (P < .0001) and a sustained rate of MRD-negativity was achieved in 48.7% vs 26.3%, respectively (P < .0001).

There was a trend of overall survival in favor of daratumumab plus VRd (HR, 0.85), with an HR of 0.69 in a sensitivity analysis adjusting for deaths related to COVID-19.

Patients in the daratumumab group had a substantially longer median duration of treatment (56.3 months) than the VRd-only group (34.3 months), with the most common reason for treatment discontinuation being disease progression.

The benefit of daratumumab was generally consistent across the study’s prespecified subgroups, and the relative dose intensity of VRd was not affected by combination with daratumumab.

In terms of safety, treatment-emergent adverse events (TEAEs) were consistent with the known profile of daratumumab and VRd, with grade 5 TEAEs comparable between the two groups after adjusting for treatment exposure.

Quality of life, as measured by EORTC QLQ-C30 score, was improved in both arms over time, with no detriment related to treatment with daratumumab.

Of note, frail patients were not included in the trial. Asked in the Q and A why they were excluded, Dr. Usmani explained that “all of these options are wonderful for our patients, and we are entering a phase where quadruplet therapies will become a mainstay for majority of patients.

“But we have to be careful as we think about not overtreating patients or giving too many side effects of therapies, and that’s why it made sense for us to exclude the frail patients.”

Along those lines, he noted that a key concern in the CEPHEUS trial was tolerance of bortezomib.

“Peripheral sensory neuropathy tends to occur in about half of the patients receiving bortezomib, and about half of that number is grade 2 or higher,” he noted in an interview.

“In some patients, the symptoms do not completely resolve. [Therefore], in transplant-ineligible patients, quadruple regimens may be more relevant for the fit or intermediate-fit patients.”

He concluded that “the CEPHEUS trial compliments the MAIA regimen in supporting a daratumumab-based quadruplet or triplet standard-of-care option across transplant-ineligible patients and those deferring transplant.”

Commenting on the study, Philippe Moreau, MD, who is president of the IMS, noted that “the CEPHEUS study is important because [determining] the best treatment upfront for elderly patients is very important.”

“We need confirmation of the very good results achieved with the IMROZ trial, which showed an estimated 5-year PFS of 63.2%, said Dr. Moreau, professor of clinical hematology and head of the translational research program in hematology and oncology at the University Hospital of Nantes, France.

“If we can achieve the same results, we will have the confirmation that quadruplet is probably here to stay,” Dr. Moreau said.

Dr. Usmani disclosed relationships with Abbvie, Amgen, BioPharma, Bristol Myers Squibb, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineOx, and Takeda.
 

A version of this article first appeared on Medscape.com.

In the treatment of patients with newly diagnosed multiple myeloma (MM) who are not eligible for stem cell transplant or are transplant-deferred, adding subcutaneous daratumumab to bortezomib/lenalidomide/dexamethasone (D-VRd) significantly improves minimal residual disease (MRD) outcomes among patients, the first results from the phase 3 CEPHEUS trial showed.

“CEPHEUS is the first phase 3 daratumumab trial with a primary endpoint of MRD negativity,” said first author Saad Z. Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York City, in presenting late-breaking findings at the annual meeting of the International Myeloma Society in Rio de Janeiro, Brazil in late September.

“We found that adding daratumumab to VRd significantly improved depth and duration of response,” Dr. Usmani said. “[The quadruplet regimen] has the potential to improve clinical outcomes for transplant-ineligible or transplant-deferred patients with newly diagnosed MM who can tolerate bortezomib.”

For newly diagnosed patients with MM who are not eligible for a stem cell transplant, the triplet MAIA regimen of daratumumab, lenalidomide, and dexamethasone is a recommended standard of care, having shown a median overall survival of 7.5 years.

However, for those who are transplant eligible, the PERSEUS regimen of D-VRd followed by daratumumab/lenalidomide maintenance, has shown significant progress-free survival benefits compared with the standard of care.

For the ongoing, multicenter, open-label CEPHEUS study, Dr. Usmani and his colleagues investigated the efficacy of the quadruplet D-VRd regimen compared with VRd alone among newly diagnosed patients who are transplant-ineligible or deferred (not planned as initial therapy).

In the trial, 395 adult patients with transplant-ineligible or transplant-deferred newly diagnosed MM all were initially treated with eight 21-day cycles of VRd, followed by 28-day cycles of lenalidomide until disease progression.

The patients were then randomized to VRd either with (n = 197) or without (n = 198) subcutaneous daratumumab.

Those receiving daratumumab received the subcutaneous therapy weekly in cycles 1 and 2, every 3 weeks in cycles 3-8, and every 4 weeks in cycles 9 or more, until disease progression.

The patients had a median age of 70 years; 28.1% had International Staging System stage III disease, and 13.2% had high-risk cytogenetics.

For the primary endpoint, with a median follow-up of 58.7 months, those in the daratumumab group had a significantly higher rate of being MRD-negative (60.9%) than the VRd-only group (39.4%; odds ratio [OR], 2.37; P < .0001).

Likewise, progression-free survival (PFS) was significantly improved with the daratumumab regimen vs VRd (hazard ratio [HR], 0.57; P = .0005).

A median PFS was not reached for daratumumab plus VRd, compared with 52.6 months for the VRd group, while estimated 54-month PFS rates were 68.1% vs 49.5%, respectively.

A complete response or better was achieved among 81.2% in the daratumumab regimen vs 61.6% with VRd alone (P < .0001) and a sustained rate of MRD-negativity was achieved in 48.7% vs 26.3%, respectively (P < .0001).

There was a trend of overall survival in favor of daratumumab plus VRd (HR, 0.85), with an HR of 0.69 in a sensitivity analysis adjusting for deaths related to COVID-19.

Patients in the daratumumab group had a substantially longer median duration of treatment (56.3 months) than the VRd-only group (34.3 months), with the most common reason for treatment discontinuation being disease progression.

The benefit of daratumumab was generally consistent across the study’s prespecified subgroups, and the relative dose intensity of VRd was not affected by combination with daratumumab.

In terms of safety, treatment-emergent adverse events (TEAEs) were consistent with the known profile of daratumumab and VRd, with grade 5 TEAEs comparable between the two groups after adjusting for treatment exposure.

Quality of life, as measured by EORTC QLQ-C30 score, was improved in both arms over time, with no detriment related to treatment with daratumumab.

Of note, frail patients were not included in the trial. Asked in the Q and A why they were excluded, Dr. Usmani explained that “all of these options are wonderful for our patients, and we are entering a phase where quadruplet therapies will become a mainstay for majority of patients.

“But we have to be careful as we think about not overtreating patients or giving too many side effects of therapies, and that’s why it made sense for us to exclude the frail patients.”

Along those lines, he noted that a key concern in the CEPHEUS trial was tolerance of bortezomib.

“Peripheral sensory neuropathy tends to occur in about half of the patients receiving bortezomib, and about half of that number is grade 2 or higher,” he noted in an interview.

“In some patients, the symptoms do not completely resolve. [Therefore], in transplant-ineligible patients, quadruple regimens may be more relevant for the fit or intermediate-fit patients.”

He concluded that “the CEPHEUS trial compliments the MAIA regimen in supporting a daratumumab-based quadruplet or triplet standard-of-care option across transplant-ineligible patients and those deferring transplant.”

Commenting on the study, Philippe Moreau, MD, who is president of the IMS, noted that “the CEPHEUS study is important because [determining] the best treatment upfront for elderly patients is very important.”

“We need confirmation of the very good results achieved with the IMROZ trial, which showed an estimated 5-year PFS of 63.2%, said Dr. Moreau, professor of clinical hematology and head of the translational research program in hematology and oncology at the University Hospital of Nantes, France.

“If we can achieve the same results, we will have the confirmation that quadruplet is probably here to stay,” Dr. Moreau said.

Dr. Usmani disclosed relationships with Abbvie, Amgen, BioPharma, Bristol Myers Squibb, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineOx, and Takeda.
 

A version of this article first appeared on Medscape.com.

In the treatment of patients with newly diagnosed multiple myeloma (MM) who are not eligible for stem cell transplant or are transplant-deferred, adding subcutaneous daratumumab to bortezomib/lenalidomide/dexamethasone (D-VRd) significantly improves minimal residual disease (MRD) outcomes among patients, the first results from the phase 3 CEPHEUS trial showed.

“CEPHEUS is the first phase 3 daratumumab trial with a primary endpoint of MRD negativity,” said first author Saad Z. Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York City, in presenting late-breaking findings at the annual meeting of the International Myeloma Society in Rio de Janeiro, Brazil in late September.

“We found that adding daratumumab to VRd significantly improved depth and duration of response,” Dr. Usmani said. “[The quadruplet regimen] has the potential to improve clinical outcomes for transplant-ineligible or transplant-deferred patients with newly diagnosed MM who can tolerate bortezomib.”

For newly diagnosed patients with MM who are not eligible for a stem cell transplant, the triplet MAIA regimen of daratumumab, lenalidomide, and dexamethasone is a recommended standard of care, having shown a median overall survival of 7.5 years.

However, for those who are transplant eligible, the PERSEUS regimen of D-VRd followed by daratumumab/lenalidomide maintenance, has shown significant progress-free survival benefits compared with the standard of care.

For the ongoing, multicenter, open-label CEPHEUS study, Dr. Usmani and his colleagues investigated the efficacy of the quadruplet D-VRd regimen compared with VRd alone among newly diagnosed patients who are transplant-ineligible or deferred (not planned as initial therapy).

In the trial, 395 adult patients with transplant-ineligible or transplant-deferred newly diagnosed MM all were initially treated with eight 21-day cycles of VRd, followed by 28-day cycles of lenalidomide until disease progression.

The patients were then randomized to VRd either with (n = 197) or without (n = 198) subcutaneous daratumumab.

Those receiving daratumumab received the subcutaneous therapy weekly in cycles 1 and 2, every 3 weeks in cycles 3-8, and every 4 weeks in cycles 9 or more, until disease progression.

The patients had a median age of 70 years; 28.1% had International Staging System stage III disease, and 13.2% had high-risk cytogenetics.

For the primary endpoint, with a median follow-up of 58.7 months, those in the daratumumab group had a significantly higher rate of being MRD-negative (60.9%) than the VRd-only group (39.4%; odds ratio [OR], 2.37; P < .0001).

Likewise, progression-free survival (PFS) was significantly improved with the daratumumab regimen vs VRd (hazard ratio [HR], 0.57; P = .0005).

A median PFS was not reached for daratumumab plus VRd, compared with 52.6 months for the VRd group, while estimated 54-month PFS rates were 68.1% vs 49.5%, respectively.

A complete response or better was achieved among 81.2% in the daratumumab regimen vs 61.6% with VRd alone (P < .0001) and a sustained rate of MRD-negativity was achieved in 48.7% vs 26.3%, respectively (P < .0001).

There was a trend of overall survival in favor of daratumumab plus VRd (HR, 0.85), with an HR of 0.69 in a sensitivity analysis adjusting for deaths related to COVID-19.

Patients in the daratumumab group had a substantially longer median duration of treatment (56.3 months) than the VRd-only group (34.3 months), with the most common reason for treatment discontinuation being disease progression.

The benefit of daratumumab was generally consistent across the study’s prespecified subgroups, and the relative dose intensity of VRd was not affected by combination with daratumumab.

In terms of safety, treatment-emergent adverse events (TEAEs) were consistent with the known profile of daratumumab and VRd, with grade 5 TEAEs comparable between the two groups after adjusting for treatment exposure.

Quality of life, as measured by EORTC QLQ-C30 score, was improved in both arms over time, with no detriment related to treatment with daratumumab.

Of note, frail patients were not included in the trial. Asked in the Q and A why they were excluded, Dr. Usmani explained that “all of these options are wonderful for our patients, and we are entering a phase where quadruplet therapies will become a mainstay for majority of patients.

“But we have to be careful as we think about not overtreating patients or giving too many side effects of therapies, and that’s why it made sense for us to exclude the frail patients.”

Along those lines, he noted that a key concern in the CEPHEUS trial was tolerance of bortezomib.

“Peripheral sensory neuropathy tends to occur in about half of the patients receiving bortezomib, and about half of that number is grade 2 or higher,” he noted in an interview.

“In some patients, the symptoms do not completely resolve. [Therefore], in transplant-ineligible patients, quadruple regimens may be more relevant for the fit or intermediate-fit patients.”

He concluded that “the CEPHEUS trial compliments the MAIA regimen in supporting a daratumumab-based quadruplet or triplet standard-of-care option across transplant-ineligible patients and those deferring transplant.”

Commenting on the study, Philippe Moreau, MD, who is president of the IMS, noted that “the CEPHEUS study is important because [determining] the best treatment upfront for elderly patients is very important.”

“We need confirmation of the very good results achieved with the IMROZ trial, which showed an estimated 5-year PFS of 63.2%, said Dr. Moreau, professor of clinical hematology and head of the translational research program in hematology and oncology at the University Hospital of Nantes, France.

“If we can achieve the same results, we will have the confirmation that quadruplet is probably here to stay,” Dr. Moreau said.

Dr. Usmani disclosed relationships with Abbvie, Amgen, BioPharma, Bristol Myers Squibb, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineOx, and Takeda.
 

A version of this article first appeared on Medscape.com.

TOPLINE:

Home-based phototherapy for plaque and guttate psoriasis is as effective as office-based phototherapy, according to results of the randomized Light Treatment Effectiveness study.

METHODOLOGY:

• The pragmatic, investigator-initiated, open-label, noninferiority, randomized trial compared the effectiveness of 12 weeks of treatment with narrow-band ultraviolet B phototherapy administered at home (n = 393) vs at the doctor’s office (n = 390).
• Overall, 783 patients with plaque or guttate psoriasis (mean age, 48 years; 48% women) were enrolled at 42 academic and private clinical dermatology practices in the United States from March 1, 2019, to December 4, 2023, and were followed up through June 2024. At baseline, the mean Physician Global Assessment (PGA) and the mean Dermatology Life Quality Index (DLQI) scores were 2.7 and 12.2, respectively.
• The two co-primary endpoints were a PGA score ≤ 1 indicating clear or almost clear skin and a DLQI score ≤ 5.

TAKEAWAY:

• At 12 weeks, a PGA score ≤ 1 was achieved in 32.8% of patients using home-based phototherapy and in 25.6% of those who received office-based phototherapy (P < .001).
• At 12 weeks, a DLQI score ≤ 5 was achieved in 52.4% and 33.6% of home- and office-treated patients, respectively (P < .001).
• Similar benefits were seen across all Fitzpatrick skin types.
• A higher percentage of patients were adherent to home-based (51.4%) vs office-based (15.9%) phototherapy (P < .001).

IN PRACTICE:

“These data support the use of home phototherapy as a first-line treatment option for psoriasis,” and “efforts are needed to make home and office phototherapy more available to patients,” said the study’s lead author.

SOURCE:

Joel M. Gelfand, MD, director of the Psoriasis and Phototherapy Treatment Center at the University of Pennsylvania, Philadelphia, presented the findings at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis meeting during the annual meeting of the European Academy of Dermatology and Venereology, with simultaneous publication in JAMA Dermatology.

LIMITATIONS:

This was an open-label trial and because of its pragmatic design, outcome data were missing. The cost of the home-based phototherapy equipment used in the study was $6040.88, which was mostly covered by Medicare, but direct costs to patients may have varied depending on their insurance plan.

DISCLOSURES:

The Patient-Centered Outcomes Research Institute funded the study. Daavlin provided and shipped machines for home-based phototherapy to patients at no cost. Dr. Gelfand disclosed serving as a consultant for AbbVie, Artax, Bristol-Myers Squibb, Boehringer Ingelheim, Celldex, and other companies. The full list of author disclosures can be found in the published study.

A version of this article first appeared on Medscape.com.

TOPLINE:

Home-based phototherapy for plaque and guttate psoriasis is as effective as office-based phototherapy, according to results of the randomized Light Treatment Effectiveness study.

METHODOLOGY:

• The pragmatic, investigator-initiated, open-label, noninferiority, randomized trial compared the effectiveness of 12 weeks of treatment with narrow-band ultraviolet B phototherapy administered at home (n = 393) vs at the doctor’s office (n = 390).
• Overall, 783 patients with plaque or guttate psoriasis (mean age, 48 years; 48% women) were enrolled at 42 academic and private clinical dermatology practices in the United States from March 1, 2019, to December 4, 2023, and were followed up through June 2024. At baseline, the mean Physician Global Assessment (PGA) and the mean Dermatology Life Quality Index (DLQI) scores were 2.7 and 12.2, respectively.
• The two co-primary endpoints were a PGA score ≤ 1 indicating clear or almost clear skin and a DLQI score ≤ 5.

TAKEAWAY:

• At 12 weeks, a PGA score ≤ 1 was achieved in 32.8% of patients using home-based phototherapy and in 25.6% of those who received office-based phototherapy (P < .001).
• At 12 weeks, a DLQI score ≤ 5 was achieved in 52.4% and 33.6% of home- and office-treated patients, respectively (P < .001).
• Similar benefits were seen across all Fitzpatrick skin types.
• A higher percentage of patients were adherent to home-based (51.4%) vs office-based (15.9%) phototherapy (P < .001).

IN PRACTICE:

“These data support the use of home phototherapy as a first-line treatment option for psoriasis,” and “efforts are needed to make home and office phototherapy more available to patients,” said the study’s lead author.

SOURCE:

Joel M. Gelfand, MD, director of the Psoriasis and Phototherapy Treatment Center at the University of Pennsylvania, Philadelphia, presented the findings at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis meeting during the annual meeting of the European Academy of Dermatology and Venereology, with simultaneous publication in JAMA Dermatology.

LIMITATIONS:

This was an open-label trial and because of its pragmatic design, outcome data were missing. The cost of the home-based phototherapy equipment used in the study was $6040.88, which was mostly covered by Medicare, but direct costs to patients may have varied depending on their insurance plan.

DISCLOSURES:

The Patient-Centered Outcomes Research Institute funded the study. Daavlin provided and shipped machines for home-based phototherapy to patients at no cost. Dr. Gelfand disclosed serving as a consultant for AbbVie, Artax, Bristol-Myers Squibb, Boehringer Ingelheim, Celldex, and other companies. The full list of author disclosures can be found in the published study.

A version of this article first appeared on Medscape.com.

TOPLINE:

Home-based phototherapy for plaque and guttate psoriasis is as effective as office-based phototherapy, according to results of the randomized Light Treatment Effectiveness study.

METHODOLOGY:

• The pragmatic, investigator-initiated, open-label, noninferiority, randomized trial compared the effectiveness of 12 weeks of treatment with narrow-band ultraviolet B phototherapy administered at home (n = 393) vs at the doctor’s office (n = 390).
• Overall, 783 patients with plaque or guttate psoriasis (mean age, 48 years; 48% women) were enrolled at 42 academic and private clinical dermatology practices in the United States from March 1, 2019, to December 4, 2023, and were followed up through June 2024. At baseline, the mean Physician Global Assessment (PGA) and the mean Dermatology Life Quality Index (DLQI) scores were 2.7 and 12.2, respectively.
• The two co-primary endpoints were a PGA score ≤ 1 indicating clear or almost clear skin and a DLQI score ≤ 5.

TAKEAWAY:

• At 12 weeks, a PGA score ≤ 1 was achieved in 32.8% of patients using home-based phototherapy and in 25.6% of those who received office-based phototherapy (P < .001).
• At 12 weeks, a DLQI score ≤ 5 was achieved in 52.4% and 33.6% of home- and office-treated patients, respectively (P < .001).
• Similar benefits were seen across all Fitzpatrick skin types.
• A higher percentage of patients were adherent to home-based (51.4%) vs office-based (15.9%) phototherapy (P < .001).

IN PRACTICE:

“These data support the use of home phototherapy as a first-line treatment option for psoriasis,” and “efforts are needed to make home and office phototherapy more available to patients,” said the study’s lead author.

SOURCE:

Joel M. Gelfand, MD, director of the Psoriasis and Phototherapy Treatment Center at the University of Pennsylvania, Philadelphia, presented the findings at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis meeting during the annual meeting of the European Academy of Dermatology and Venereology, with simultaneous publication in JAMA Dermatology.

LIMITATIONS:

This was an open-label trial and because of its pragmatic design, outcome data were missing. The cost of the home-based phototherapy equipment used in the study was $6040.88, which was mostly covered by Medicare, but direct costs to patients may have varied depending on their insurance plan.

DISCLOSURES:

The Patient-Centered Outcomes Research Institute funded the study. Daavlin provided and shipped machines for home-based phototherapy to patients at no cost. Dr. Gelfand disclosed serving as a consultant for AbbVie, Artax, Bristol-Myers Squibb, Boehringer Ingelheim, Celldex, and other companies. The full list of author disclosures can be found in the published study.

A version of this article first appeared on Medscape.com.

DUBLIN – As healthcare systems across Europe deal with an increasing prevalence of cognitive impairment, family doctors are emerging as key players in assessing and supporting patients’ decision-making capacities. 

This was a central theme at the 29th WONCA Europe Conference, where the European Young Family Doctors Movement (EYFDM) presented insights from a project conducted across Europe, involving young general practitioners who participated in workshops held in multiple countries.

“Family doctors are the linchpin in these decisions,” said Alina Zidaru, MD, from the Irish College of Physicians, Dublin. “They understand the patient’s history, build long-term relationships, and are best positioned to ensure that decisions reflect the patient’s values, not just what the law or the family might say.”

Dr. Zidaru and her colleague, Nick Mamo, MD, member of EYFDM in Glasgow, Scotland, emphasized the central role family doctors play in ensuring that patient rights and preferences are respected, regardless of their cognitive state. They are often the first to identify cognitive impairments and must carefully navigate the legal and ethical landscape of decision-making support.

“Often, we focus too much on avoiding harm and overlook the principle of autonomy,” said Dr. Mamo. “But it’s essential to give patients the right to make their own decisions, even when those decisions might seem unwise to us.”
 

The Case of Jay

Dr. Zidaru said: “We’ve conducted workshops in Brussels, Vienna, and Sydney, focusing on how to build habits that support patients. We presented real-life cases, like Jay, a 43-year-old man with trisomy and a moderate intellectual disability who must decide whether to undergo surgery for a hernia. The most significant challenge was ensuring continuity of care and respecting his autonomy, despite cognitive limitations.”

Jay’s case illustrates the complex ethical dilemmas faced by family doctors when balancing autonomy with patient safety. In many cases, cognitive impairments raise concerns about whether a patient can make decisions independently. 

During the session, the audience was asked to share their thoughts on the case and to indicate whether they would allow Jay to make his own decision, and if they felt confident in assessing his cognitive capacity. The responses revealed a range of mixed feelings. 
 

Legal and Cultural Variations Across Europe

The session also explored how different European countries approach decision-making for cognitively impaired individuals. A clear divide exists between nations that give family members automatic decision-making rights and those that require legal appointments. 

In the United Kingdom, the Mental Capacity Act 2005 presumes capacity unless proven otherwise. Family doctors can assess patients’ decision-making abilities using any validated tool they find suitable. They should also aim to ensure that decisions are made in the patient’s best interests if they lack capacity. Family members only have legal authority if appointed through formal means, such as a lasting power of attorney.

In Spain and Italy, functional assessments are performed when patients retain decision-making authority in areas where they demonstrate competence. Legal guardianship can be appointed by the courts, sometimes limited to specific areas, but it is intended to support rather than replace the patient’s autonomy. 

In France and Portugal, guardianship may be implemented in specific domains, but the patient’s ability to participate in decisions is always prioritized. 

In Turkey, according to Turkish general practitioners in the audience, the courts and close family members often share the decision-making responsibility.

Dr. Zidaru added that Ireland’s Assisted Decision-Making (Capacity) Act 2015 introduced significant changes to how cognitive impairment is managed there. “Ireland adopted a standardized functional test of capacity, used by any doctor. A person can still make decisions as long as they understand, retain, and weigh the information needed to make that choice. If their capacity diminishes, a decision-making assistant, co–decision-maker, or representative can be appointed, but the patient’s will and preferences always come first.”
 

Family Doctors, a Growing Responsibility

“It’s not just about the legal framework: it’s about cultural awareness and early communication,” added Dr. Mamo. “We have to ask ourselves: Do patients have the right to make bad decisions? And how do we, as family doctors, respect that while still ensuring their safety?”

The session concluded with a discussion on how the role of family doctors in decision-making for cognitively impaired patients will evolve as populations age and the incidence of conditions like dementia increases. The workload is rising, and the need for clear, consistent guidelines is critical.

“Family doctors will continue to play a central role in managing these challenges,” Dr. Zidaru emphasized. “But we need more resources, more education, and more support to ensure we can respect patient autonomy without compromising their well-being.”

A version of this article first appeared on Medscape.com.

DUBLIN – As healthcare systems across Europe deal with an increasing prevalence of cognitive impairment, family doctors are emerging as key players in assessing and supporting patients’ decision-making capacities. 

This was a central theme at the 29th WONCA Europe Conference, where the European Young Family Doctors Movement (EYFDM) presented insights from a project conducted across Europe, involving young general practitioners who participated in workshops held in multiple countries.

“Family doctors are the linchpin in these decisions,” said Alina Zidaru, MD, from the Irish College of Physicians, Dublin. “They understand the patient’s history, build long-term relationships, and are best positioned to ensure that decisions reflect the patient’s values, not just what the law or the family might say.”

Dr. Zidaru and her colleague, Nick Mamo, MD, member of EYFDM in Glasgow, Scotland, emphasized the central role family doctors play in ensuring that patient rights and preferences are respected, regardless of their cognitive state. They are often the first to identify cognitive impairments and must carefully navigate the legal and ethical landscape of decision-making support.

“Often, we focus too much on avoiding harm and overlook the principle of autonomy,” said Dr. Mamo. “But it’s essential to give patients the right to make their own decisions, even when those decisions might seem unwise to us.”
 

The Case of Jay

Dr. Zidaru said: “We’ve conducted workshops in Brussels, Vienna, and Sydney, focusing on how to build habits that support patients. We presented real-life cases, like Jay, a 43-year-old man with trisomy and a moderate intellectual disability who must decide whether to undergo surgery for a hernia. The most significant challenge was ensuring continuity of care and respecting his autonomy, despite cognitive limitations.”

Jay’s case illustrates the complex ethical dilemmas faced by family doctors when balancing autonomy with patient safety. In many cases, cognitive impairments raise concerns about whether a patient can make decisions independently. 

During the session, the audience was asked to share their thoughts on the case and to indicate whether they would allow Jay to make his own decision, and if they felt confident in assessing his cognitive capacity. The responses revealed a range of mixed feelings. 
 

Legal and Cultural Variations Across Europe

The session also explored how different European countries approach decision-making for cognitively impaired individuals. A clear divide exists between nations that give family members automatic decision-making rights and those that require legal appointments. 

In the United Kingdom, the Mental Capacity Act 2005 presumes capacity unless proven otherwise. Family doctors can assess patients’ decision-making abilities using any validated tool they find suitable. They should also aim to ensure that decisions are made in the patient’s best interests if they lack capacity. Family members only have legal authority if appointed through formal means, such as a lasting power of attorney.

In Spain and Italy, functional assessments are performed when patients retain decision-making authority in areas where they demonstrate competence. Legal guardianship can be appointed by the courts, sometimes limited to specific areas, but it is intended to support rather than replace the patient’s autonomy. 

In France and Portugal, guardianship may be implemented in specific domains, but the patient’s ability to participate in decisions is always prioritized. 

In Turkey, according to Turkish general practitioners in the audience, the courts and close family members often share the decision-making responsibility.

Dr. Zidaru added that Ireland’s Assisted Decision-Making (Capacity) Act 2015 introduced significant changes to how cognitive impairment is managed there. “Ireland adopted a standardized functional test of capacity, used by any doctor. A person can still make decisions as long as they understand, retain, and weigh the information needed to make that choice. If their capacity diminishes, a decision-making assistant, co–decision-maker, or representative can be appointed, but the patient’s will and preferences always come first.”
 

Family Doctors, a Growing Responsibility

“It’s not just about the legal framework: it’s about cultural awareness and early communication,” added Dr. Mamo. “We have to ask ourselves: Do patients have the right to make bad decisions? And how do we, as family doctors, respect that while still ensuring their safety?”

The session concluded with a discussion on how the role of family doctors in decision-making for cognitively impaired patients will evolve as populations age and the incidence of conditions like dementia increases. The workload is rising, and the need for clear, consistent guidelines is critical.

“Family doctors will continue to play a central role in managing these challenges,” Dr. Zidaru emphasized. “But we need more resources, more education, and more support to ensure we can respect patient autonomy without compromising their well-being.”

A version of this article first appeared on Medscape.com.

DUBLIN – As healthcare systems across Europe deal with an increasing prevalence of cognitive impairment, family doctors are emerging as key players in assessing and supporting patients’ decision-making capacities. 

This was a central theme at the 29th WONCA Europe Conference, where the European Young Family Doctors Movement (EYFDM) presented insights from a project conducted across Europe, involving young general practitioners who participated in workshops held in multiple countries.

“Family doctors are the linchpin in these decisions,” said Alina Zidaru, MD, from the Irish College of Physicians, Dublin. “They understand the patient’s history, build long-term relationships, and are best positioned to ensure that decisions reflect the patient’s values, not just what the law or the family might say.”

Dr. Zidaru and her colleague, Nick Mamo, MD, member of EYFDM in Glasgow, Scotland, emphasized the central role family doctors play in ensuring that patient rights and preferences are respected, regardless of their cognitive state. They are often the first to identify cognitive impairments and must carefully navigate the legal and ethical landscape of decision-making support.

“Often, we focus too much on avoiding harm and overlook the principle of autonomy,” said Dr. Mamo. “But it’s essential to give patients the right to make their own decisions, even when those decisions might seem unwise to us.”
 

The Case of Jay

Dr. Zidaru said: “We’ve conducted workshops in Brussels, Vienna, and Sydney, focusing on how to build habits that support patients. We presented real-life cases, like Jay, a 43-year-old man with trisomy and a moderate intellectual disability who must decide whether to undergo surgery for a hernia. The most significant challenge was ensuring continuity of care and respecting his autonomy, despite cognitive limitations.”

Jay’s case illustrates the complex ethical dilemmas faced by family doctors when balancing autonomy with patient safety. In many cases, cognitive impairments raise concerns about whether a patient can make decisions independently. 

During the session, the audience was asked to share their thoughts on the case and to indicate whether they would allow Jay to make his own decision, and if they felt confident in assessing his cognitive capacity. The responses revealed a range of mixed feelings. 
 

Legal and Cultural Variations Across Europe

The session also explored how different European countries approach decision-making for cognitively impaired individuals. A clear divide exists between nations that give family members automatic decision-making rights and those that require legal appointments. 

In the United Kingdom, the Mental Capacity Act 2005 presumes capacity unless proven otherwise. Family doctors can assess patients’ decision-making abilities using any validated tool they find suitable. They should also aim to ensure that decisions are made in the patient’s best interests if they lack capacity. Family members only have legal authority if appointed through formal means, such as a lasting power of attorney.

In Spain and Italy, functional assessments are performed when patients retain decision-making authority in areas where they demonstrate competence. Legal guardianship can be appointed by the courts, sometimes limited to specific areas, but it is intended to support rather than replace the patient’s autonomy. 

In France and Portugal, guardianship may be implemented in specific domains, but the patient’s ability to participate in decisions is always prioritized. 

In Turkey, according to Turkish general practitioners in the audience, the courts and close family members often share the decision-making responsibility.

Dr. Zidaru added that Ireland’s Assisted Decision-Making (Capacity) Act 2015 introduced significant changes to how cognitive impairment is managed there. “Ireland adopted a standardized functional test of capacity, used by any doctor. A person can still make decisions as long as they understand, retain, and weigh the information needed to make that choice. If their capacity diminishes, a decision-making assistant, co–decision-maker, or representative can be appointed, but the patient’s will and preferences always come first.”
 

Family Doctors, a Growing Responsibility

“It’s not just about the legal framework: it’s about cultural awareness and early communication,” added Dr. Mamo. “We have to ask ourselves: Do patients have the right to make bad decisions? And how do we, as family doctors, respect that while still ensuring their safety?”

The session concluded with a discussion on how the role of family doctors in decision-making for cognitively impaired patients will evolve as populations age and the incidence of conditions like dementia increases. The workload is rising, and the need for clear, consistent guidelines is critical.

“Family doctors will continue to play a central role in managing these challenges,” Dr. Zidaru emphasized. “But we need more resources, more education, and more support to ensure we can respect patient autonomy without compromising their well-being.”

A version of this article first appeared on Medscape.com.

COPENHAGEN — Growing evidence supports the use of highly effective disease-modifying therapies for children with multiple sclerosis (MS). However, only few of these medications are licensed for pediatric use, indicating it may be time to reconsider the standard treatment approach for this patient population.

Treatments for pediatric-onset MS have mostly been used off-label until the recent approvals of fingolimod, dimethyl fumarate, and teriflunomide. Typically, children with MS start with moderately effective therapies, while more potent options are reserved for those who don’t respond.

However, recent research suggests this may not be the most effective treatment strategy for this patient population. Several studies suggesting impressive treatment responses to highly effective therapies (HETs) in children were presented at the 2024 ECTRIMS annual meeting.

In one study, initiating monoclonal antibody treatment during childhood was associated with reduced disability into early adulthood and beyond.

“Our findings are a strong argument for rethinking current treatment guidelines,” said study investigator Sifat Sharmin, PhD, The University of Melbourne, Australia.

“By allowing earlier access to highly effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability,” she added.

In another presentation, Yael Hacohen, MD, Great Ormond Street Hospital, London, England, noted that the use of these more effective monoclonal antibody therapies in children with MS has been associated with some improvements in Expanded Disability Status Scale (EDSS) scores after 2 or 3 years of treatment.

Maybe this is a sign that “this is a population that can repair, in contrast to adult patients,” she wondered.

MS is primarily a disease of adults, but pediatric MS accounts for up to 5% of all cases. Children with MS tend to have much more active disease than adults, Dr. Hacohen explained. However, they also tend to recover from attacks more quickly with little disability, which sometimes causes diagnostic delays.

A pediatrician or family doctor will often dismiss pins and needles or blurred vision that only lasts a couple of days and won’t send the patient for an MRI, she said. But on MRI, pediatric patients with MS often have multiple lesions, even though they may have had very few symptoms. The EDSS may not change very much, but there can still be significant brain atrophy.

Over the past 20 years, there’s been an explosion of new disease-modifying treatments for MS, but these high-efficacy treatments, such as antibody therapies, are often not prescribed until the patient reaches the age of 18 years, both Dr. Sharmin and Dr. Hacohen pointed out.

“We need to get some of these medications approved for use in children,” Dr. Hacohen said.
 

Slowed Disability

In her presentation, Dr. Sharmin reported an observational study that included 282 patients younger than 18 years at MS onset identified from the French MS Registry, the Italian MS Register, and the Global MSBase Registry.

Of these, 110 (39%) had initiated therapy with ocrelizumab, rituximab, or natalizumab early in the disease course between ages 12 and 17 years and 172 (61%) had initiated treatment with one of these agents at ages 20-22 years.

The primary outcome was the difference in EDSS scores from baseline (at age 18 years) to ages 23-27 years between those who had started treatment with one of these agents early and those who had started late.

At the baseline of age 18 years, the median EDSS score was 1.5 in the early group and 1.3 in the late group. Median follow-up time was 10.8 years.

The data were adjusted for baseline differences in factors such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses (using inverse probability treatment weighting based on propensity scores).

Results showed that between ages 23 and 27 years, disability was a 0.57 step lower in the early group than in the late group. The mean absolute differences in EDSS from baseline were 0.40 in the early group and 0.95 in the late group. This benefit of early treatment persisted throughout the rest of the follow-up period.

The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97%, Dr. Sharmin noted.

“Starting these highly effective therapies, before the onset of significant neurological impairments, appears crucial for preserving neurological function in children with relapsing-remitting MS over the long term,” she said.

These findings highlight the critical importance of early intervention in pediatric-onset MS, she concluded.

The researchers are planning further work to generate more evidence to support the proactive treatment of pediatric-onset MS, with a particular focus on assessing the long-term risks for immunosuppressive therapies in this population.
 

Ocrelizumab Experience in Children

Dr. Hacohen reported on a UK cohort of children with MS treated with ocrelizumab, with 66 patients having more than 12 months of follow-up. Of these, only four patients had relapses, and there was no evidence of disease activity in 94% patients.

“We’ve stopped doing relapse clinic because they really don’t relapse,” Dr. Hacohen reported.

“This has completely changed our practice in pediatric MS,” she said. Twice a year, patients come in to have pre-infusion bloods and clinical assessments and then return a month later for treatment.

“They only have to come to the hospital for 4 days a year, and the rest of the time, they can forget they have MS,” said Dr. Hacohen.

In terms of complications, one patient in the UK cohort developed enterovirus meningitis but recovered completely, and two patients had hypogammaglobulinemia and were changed to an extended interval or to a different agent.

Dr. Hacohen cautioned that hypogammaglobulinemia — a condition in which immunoglobulin levels are below normal — is “something that hypothetically we should maybe be more worried about in the pediatric population, particularly as these patients are more likely to be on anti-CD20 therapies for a much longer time.”

She said this complication tends to happen after about 4 or 5 years of treatment. “If we start seeing IgG levels dropping, we need to come up with a plan about extending the dosing interval. We need clinical trials to look at this.”

Dr. Hacohen also drew attention to the issue of vaccinations not being effective in patients on anti-CD20 antibody therapy, which could be a particular problem in children.

However, given that vaccinations do seem to be effective in patients taking natalizumab, pediatric patients with highly active disease could receive the drug for 3-6 months while receiving vaccines and then switched over to ocrelizumab, she said.

Giving natalizumab for such a short period is not believed to have a high risk of developing JCV antibodies, she added.

In another presentation, Brenda Banwell, MD, Johns Hopkins Children’s Center, Baltimore, reported new data from an early study (OPERETTA 1) with ocrelizumab in pediatric relapsing-remitting MS showing a safety profile similar to that observed in adults. The suggested dose is 300 mg for children under 35 kg and 600 mg for adults over 35 kg, administered every 24 weeks. These doses will be further investigated in the ongoing phase III OPERETTA 2 trial.

Dr. Sharmin received a postdoctoral fellowship from MS Australia. The OPERETTA studies were sponsored by F. Hoffmann-La Roche. Dr. Banwell served as a consultant to Roche. Dr. Hacohen reported no relevant disclosures.
 

A version of this article first appeared on Medscape.com.

COPENHAGEN — Growing evidence supports the use of highly effective disease-modifying therapies for children with multiple sclerosis (MS). However, only few of these medications are licensed for pediatric use, indicating it may be time to reconsider the standard treatment approach for this patient population.

Treatments for pediatric-onset MS have mostly been used off-label until the recent approvals of fingolimod, dimethyl fumarate, and teriflunomide. Typically, children with MS start with moderately effective therapies, while more potent options are reserved for those who don’t respond.

However, recent research suggests this may not be the most effective treatment strategy for this patient population. Several studies suggesting impressive treatment responses to highly effective therapies (HETs) in children were presented at the 2024 ECTRIMS annual meeting.

In one study, initiating monoclonal antibody treatment during childhood was associated with reduced disability into early adulthood and beyond.

“Our findings are a strong argument for rethinking current treatment guidelines,” said study investigator Sifat Sharmin, PhD, The University of Melbourne, Australia.

“By allowing earlier access to highly effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability,” she added.

In another presentation, Yael Hacohen, MD, Great Ormond Street Hospital, London, England, noted that the use of these more effective monoclonal antibody therapies in children with MS has been associated with some improvements in Expanded Disability Status Scale (EDSS) scores after 2 or 3 years of treatment.

Maybe this is a sign that “this is a population that can repair, in contrast to adult patients,” she wondered.

MS is primarily a disease of adults, but pediatric MS accounts for up to 5% of all cases. Children with MS tend to have much more active disease than adults, Dr. Hacohen explained. However, they also tend to recover from attacks more quickly with little disability, which sometimes causes diagnostic delays.

A pediatrician or family doctor will often dismiss pins and needles or blurred vision that only lasts a couple of days and won’t send the patient for an MRI, she said. But on MRI, pediatric patients with MS often have multiple lesions, even though they may have had very few symptoms. The EDSS may not change very much, but there can still be significant brain atrophy.

Over the past 20 years, there’s been an explosion of new disease-modifying treatments for MS, but these high-efficacy treatments, such as antibody therapies, are often not prescribed until the patient reaches the age of 18 years, both Dr. Sharmin and Dr. Hacohen pointed out.

“We need to get some of these medications approved for use in children,” Dr. Hacohen said.
 

Slowed Disability

In her presentation, Dr. Sharmin reported an observational study that included 282 patients younger than 18 years at MS onset identified from the French MS Registry, the Italian MS Register, and the Global MSBase Registry.

Of these, 110 (39%) had initiated therapy with ocrelizumab, rituximab, or natalizumab early in the disease course between ages 12 and 17 years and 172 (61%) had initiated treatment with one of these agents at ages 20-22 years.

The primary outcome was the difference in EDSS scores from baseline (at age 18 years) to ages 23-27 years between those who had started treatment with one of these agents early and those who had started late.

At the baseline of age 18 years, the median EDSS score was 1.5 in the early group and 1.3 in the late group. Median follow-up time was 10.8 years.

The data were adjusted for baseline differences in factors such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses (using inverse probability treatment weighting based on propensity scores).

Results showed that between ages 23 and 27 years, disability was a 0.57 step lower in the early group than in the late group. The mean absolute differences in EDSS from baseline were 0.40 in the early group and 0.95 in the late group. This benefit of early treatment persisted throughout the rest of the follow-up period.

The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97%, Dr. Sharmin noted.

“Starting these highly effective therapies, before the onset of significant neurological impairments, appears crucial for preserving neurological function in children with relapsing-remitting MS over the long term,” she said.

These findings highlight the critical importance of early intervention in pediatric-onset MS, she concluded.

The researchers are planning further work to generate more evidence to support the proactive treatment of pediatric-onset MS, with a particular focus on assessing the long-term risks for immunosuppressive therapies in this population.
 

Ocrelizumab Experience in Children

Dr. Hacohen reported on a UK cohort of children with MS treated with ocrelizumab, with 66 patients having more than 12 months of follow-up. Of these, only four patients had relapses, and there was no evidence of disease activity in 94% patients.

“We’ve stopped doing relapse clinic because they really don’t relapse,” Dr. Hacohen reported.

“This has completely changed our practice in pediatric MS,” she said. Twice a year, patients come in to have pre-infusion bloods and clinical assessments and then return a month later for treatment.

“They only have to come to the hospital for 4 days a year, and the rest of the time, they can forget they have MS,” said Dr. Hacohen.

In terms of complications, one patient in the UK cohort developed enterovirus meningitis but recovered completely, and two patients had hypogammaglobulinemia and were changed to an extended interval or to a different agent.

Dr. Hacohen cautioned that hypogammaglobulinemia — a condition in which immunoglobulin levels are below normal — is “something that hypothetically we should maybe be more worried about in the pediatric population, particularly as these patients are more likely to be on anti-CD20 therapies for a much longer time.”

She said this complication tends to happen after about 4 or 5 years of treatment. “If we start seeing IgG levels dropping, we need to come up with a plan about extending the dosing interval. We need clinical trials to look at this.”

Dr. Hacohen also drew attention to the issue of vaccinations not being effective in patients on anti-CD20 antibody therapy, which could be a particular problem in children.

However, given that vaccinations do seem to be effective in patients taking natalizumab, pediatric patients with highly active disease could receive the drug for 3-6 months while receiving vaccines and then switched over to ocrelizumab, she said.

Giving natalizumab for such a short period is not believed to have a high risk of developing JCV antibodies, she added.

In another presentation, Brenda Banwell, MD, Johns Hopkins Children’s Center, Baltimore, reported new data from an early study (OPERETTA 1) with ocrelizumab in pediatric relapsing-remitting MS showing a safety profile similar to that observed in adults. The suggested dose is 300 mg for children under 35 kg and 600 mg for adults over 35 kg, administered every 24 weeks. These doses will be further investigated in the ongoing phase III OPERETTA 2 trial.

Dr. Sharmin received a postdoctoral fellowship from MS Australia. The OPERETTA studies were sponsored by F. Hoffmann-La Roche. Dr. Banwell served as a consultant to Roche. Dr. Hacohen reported no relevant disclosures.
 

A version of this article first appeared on Medscape.com.

COPENHAGEN — Growing evidence supports the use of highly effective disease-modifying therapies for children with multiple sclerosis (MS). However, only few of these medications are licensed for pediatric use, indicating it may be time to reconsider the standard treatment approach for this patient population.

Treatments for pediatric-onset MS have mostly been used off-label until the recent approvals of fingolimod, dimethyl fumarate, and teriflunomide. Typically, children with MS start with moderately effective therapies, while more potent options are reserved for those who don’t respond.

However, recent research suggests this may not be the most effective treatment strategy for this patient population. Several studies suggesting impressive treatment responses to highly effective therapies (HETs) in children were presented at the 2024 ECTRIMS annual meeting.

In one study, initiating monoclonal antibody treatment during childhood was associated with reduced disability into early adulthood and beyond.

“Our findings are a strong argument for rethinking current treatment guidelines,” said study investigator Sifat Sharmin, PhD, The University of Melbourne, Australia.

“By allowing earlier access to highly effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability,” she added.

In another presentation, Yael Hacohen, MD, Great Ormond Street Hospital, London, England, noted that the use of these more effective monoclonal antibody therapies in children with MS has been associated with some improvements in Expanded Disability Status Scale (EDSS) scores after 2 or 3 years of treatment.

Maybe this is a sign that “this is a population that can repair, in contrast to adult patients,” she wondered.

MS is primarily a disease of adults, but pediatric MS accounts for up to 5% of all cases. Children with MS tend to have much more active disease than adults, Dr. Hacohen explained. However, they also tend to recover from attacks more quickly with little disability, which sometimes causes diagnostic delays.

A pediatrician or family doctor will often dismiss pins and needles or blurred vision that only lasts a couple of days and won’t send the patient for an MRI, she said. But on MRI, pediatric patients with MS often have multiple lesions, even though they may have had very few symptoms. The EDSS may not change very much, but there can still be significant brain atrophy.

Over the past 20 years, there’s been an explosion of new disease-modifying treatments for MS, but these high-efficacy treatments, such as antibody therapies, are often not prescribed until the patient reaches the age of 18 years, both Dr. Sharmin and Dr. Hacohen pointed out.

“We need to get some of these medications approved for use in children,” Dr. Hacohen said.
 

Slowed Disability

In her presentation, Dr. Sharmin reported an observational study that included 282 patients younger than 18 years at MS onset identified from the French MS Registry, the Italian MS Register, and the Global MSBase Registry.

Of these, 110 (39%) had initiated therapy with ocrelizumab, rituximab, or natalizumab early in the disease course between ages 12 and 17 years and 172 (61%) had initiated treatment with one of these agents at ages 20-22 years.

The primary outcome was the difference in EDSS scores from baseline (at age 18 years) to ages 23-27 years between those who had started treatment with one of these agents early and those who had started late.

At the baseline of age 18 years, the median EDSS score was 1.5 in the early group and 1.3 in the late group. Median follow-up time was 10.8 years.

The data were adjusted for baseline differences in factors such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses (using inverse probability treatment weighting based on propensity scores).

Results showed that between ages 23 and 27 years, disability was a 0.57 step lower in the early group than in the late group. The mean absolute differences in EDSS from baseline were 0.40 in the early group and 0.95 in the late group. This benefit of early treatment persisted throughout the rest of the follow-up period.

The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97%, Dr. Sharmin noted.

“Starting these highly effective therapies, before the onset of significant neurological impairments, appears crucial for preserving neurological function in children with relapsing-remitting MS over the long term,” she said.

These findings highlight the critical importance of early intervention in pediatric-onset MS, she concluded.

The researchers are planning further work to generate more evidence to support the proactive treatment of pediatric-onset MS, with a particular focus on assessing the long-term risks for immunosuppressive therapies in this population.
 

Ocrelizumab Experience in Children

Dr. Hacohen reported on a UK cohort of children with MS treated with ocrelizumab, with 66 patients having more than 12 months of follow-up. Of these, only four patients had relapses, and there was no evidence of disease activity in 94% patients.

“We’ve stopped doing relapse clinic because they really don’t relapse,” Dr. Hacohen reported.

“This has completely changed our practice in pediatric MS,” she said. Twice a year, patients come in to have pre-infusion bloods and clinical assessments and then return a month later for treatment.

“They only have to come to the hospital for 4 days a year, and the rest of the time, they can forget they have MS,” said Dr. Hacohen.

In terms of complications, one patient in the UK cohort developed enterovirus meningitis but recovered completely, and two patients had hypogammaglobulinemia and were changed to an extended interval or to a different agent.

Dr. Hacohen cautioned that hypogammaglobulinemia — a condition in which immunoglobulin levels are below normal — is “something that hypothetically we should maybe be more worried about in the pediatric population, particularly as these patients are more likely to be on anti-CD20 therapies for a much longer time.”

She said this complication tends to happen after about 4 or 5 years of treatment. “If we start seeing IgG levels dropping, we need to come up with a plan about extending the dosing interval. We need clinical trials to look at this.”

Dr. Hacohen also drew attention to the issue of vaccinations not being effective in patients on anti-CD20 antibody therapy, which could be a particular problem in children.

However, given that vaccinations do seem to be effective in patients taking natalizumab, pediatric patients with highly active disease could receive the drug for 3-6 months while receiving vaccines and then switched over to ocrelizumab, she said.

Giving natalizumab for such a short period is not believed to have a high risk of developing JCV antibodies, she added.

In another presentation, Brenda Banwell, MD, Johns Hopkins Children’s Center, Baltimore, reported new data from an early study (OPERETTA 1) with ocrelizumab in pediatric relapsing-remitting MS showing a safety profile similar to that observed in adults. The suggested dose is 300 mg for children under 35 kg and 600 mg for adults over 35 kg, administered every 24 weeks. These doses will be further investigated in the ongoing phase III OPERETTA 2 trial.

Dr. Sharmin received a postdoctoral fellowship from MS Australia. The OPERETTA studies were sponsored by F. Hoffmann-La Roche. Dr. Banwell served as a consultant to Roche. Dr. Hacohen reported no relevant disclosures.
 

A version of this article first appeared on Medscape.com.

PHILADELPHIA — The investigational agent ecopipam reduces tic severity in children and adolescents with Tourette syndrome without exacerbating common psychiatric comorbidities, results of a new analysis suggest.

As previously reported, the first-in-class dopamine-1 (D1) receptor antagonist reduced the primary endpoint of tic severity scores by 30% compared with placebo among 149 patients in the 12-week, phase 2b D1AMOND trial. 

What was unknown, however, is whether ecopipam would affect the comorbidities of attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder (OCD), and depression that were present in two thirds of participants.

The two key findings in this post hoc analysis were “first, that patients with a nonmotor diagnosis like depression or ADHD did not do any worse in terms of tic efficacy; and second, we didn’t find any evidence that any of the nonmotor symptoms of Tourette’s got worse with ecopipam,” said study investigator Donald Gilbert, MD, professor of pediatrics and neurology at University of Cincinnati Children’s Hospital Medical Center.

Dr. Gilbert presented the results at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024. 
 

No Worsening of ADHD Symptoms

Tourette syndrome affects approximately 1 in 160 children between 5 and 17 years of age in the United States, data from the Tourette Association of America show. Research has shown that 85% of patients with Tourette syndrome will have a co-occurring psychiatric condition. 

Guidelines recommend Comprehensive Behavioral Intervention for Tics (CBIT) as first-line treatment for Tourette syndrome, but cost and access are barriers. The only currently approved medications to treat Tourette syndrome are antipsychotics that act on the D2 receptor, but their use is limited by the potential for weight gain, metabolic changes, drug-induced movement disorders, and risk for suicidality, said Dr. Gilbert. 

The D1AMOND study randomly assigned patients aged 6-17 years with Tourette syndrome and a Yale Global Tic Severity Total Tic Scale score of at least 20 to receive a target steady-state dose of 2 mg/kg/d of oral ecopipam or placebo for a 4-week titration period, followed by an 8-week treatment phase before being tapered off the study drug. 

Patients were allowed to remain on medications without D2-receptor blocking activity for anxiety, OCD, and ADHD if the dosage was stable for 4 weeks before screening and not specifically prescribed for tics. 

A mixed model for repeated measures was used to assess changes in several scales administered at baseline and at weeks 4, 6, 8, and 12: the Swanson, Nolan, and Pelham Teacher and Parent Rating Scale (SNAP-IV); Pediatric Anxiety Rating Scale; Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), and Children’s Depression Rating Scale–Revised (CDRS-R). 

In patients with a co-occurring psychiatric condition, no significant differences were found over time between ecopipam and placebo in terms of SNAP-IV (-4.4; P = .45), Pediatric Anxiety Rating Scale (1.0; P = .62), CDRS-R (-3.2; P = .65), or CY-BOCS (-0.7; P = .76) scores.

For ADHD, the most frequent comorbidity, scores trended lower in the ecopipam group but were not significantly different from those in the placebo group. “We found no evidence that ecopipam worsened ADHD symptoms,” Dr. Gilbert said.
 

No Weight Gain

Suicidal ideation was reported during the dosing period in eight patients in the placebo group and none in the ecopipam group. One patient treated with ecopipam had multiple depressive episodes and dropped out of the study on day 79. Ecopipam was discontinued in another patient because of anxiety. 

Notably, there was more weight gain in the placebo group than in the ecopipam group (2.4 kg vs 1.8 kg) by 12 weeks. No shifts from baseline were seen in blood glucose, A1c, total cholesterol, or triglycerides in either group. 

The lack of weight gain with ecopipam is important, Dr. Gilbert stressed. “Medicines that block D2 so often cause weight gain, and a lot of our patients, unfortunately, can be heavier already,” he explained. “We don’t want to make that worse or put them at a long-term risk of type 2 diabetes.”  

For patients with more severe disease, we really “do need something else besides D2-blockers in our tool kit,” he added. 

Commenting on the study, Tanya Simuni, MD, co-moderator of the session and director of the Parkinson’s Disease and Movement Disorders Center, Northwestern Feinberg School of Medicine, Chicago, said the aim of assessing D1-directed medications is to reduce the negative impact of traditional antipsychotics with a theoretical benefit on hyperkinetic movement.

But the most important thing that they’ve shown is that “there was no negative effect, no liability for the nonmotor manifestations of Tourette’s. That is important because Tourette’s is not a pure motor syndrome, and psychiatric manifestations in a lot of cases are associated with more disease-related quality of life impairment compared to the motor manifestations,” said Dr. Simuni.

That said, she noted, the “ideal drug would be the one that would have benefit for both motor and nonmotor domains.” 
 

Multiple Agents in the Pipeline 

“The neuropharmacology of Tourette syndrome has long remained stagnant, and most existing treatments often fail to balance efficacy with tolerability, underscoring the urgent need for newer therapeutics,” Christos Ganos, MD, professor of neurology, University of Toronto, said in a press release.

He noted that three studies have been published on ecopipam since 2014: an 8-week, open-label trial in adults with Tourette syndrome, a 4-week, placebo-controlled crossover trial in 38 children with Tourette syndrome, and the 12-week D1AMOND trial.

“These studies demonstrated clinically meaningful reductions in tics, without relevant safety concerns or changes in Tourette syndrome-typical neuropsychiatric measures, as also shown by the abstract highlighted here,” Dr. Ganos said. 

“This emerging body of research provides a solid foundation for introducing ecopipam as a novel pharmacological agent to treat tics and may motivate further work, both on the pathophysiology and pharmacotherapy of tic disorders and their associations.”

A single-arm, phase 3 trial is currently underway at 58 centers in North America and Europe investigating the long-term safety and tolerability of ecopipam over 24 months in 150 children, adolescents, and adults with Tourette syndrome. The study is expected to be completed in 2027.

Several other new medications are also under investigation including the vesicular monoamine transporter (VMAT2) inhibitors tetrabenazine, deutetrabenazine, and valbenazine; the PEDE10A inhibitor gemlapodect; the allopregnanolone antagonist sepranolone; and SCI-110, which combines dronabinol (the synthetic form of tetrahydrocannabinol) and the endocannabinoid palmitoylethanolamide.

The study was funded by Emalex Biosciences. Dr. Gilbert’s institution received research support from Emalex Biosciences and PTC Therapeutics. Dr. Gilbert has received publishing royalties from a healthcare-related publication; compensation for serving as a medical expert with Teladoc; Advanced Medical; and the National Vaccine Injury Compensation Program, US Department of Health and Human Services. Simuni reports no relevant conflicts of interest. Dr. Ganos has received honoraria for educational activities from the Movement Disorder Society and academic research support from VolkswagenStiftung. 
 

A version of this article first appeared on Medscape.com.

PHILADELPHIA — The investigational agent ecopipam reduces tic severity in children and adolescents with Tourette syndrome without exacerbating common psychiatric comorbidities, results of a new analysis suggest.

As previously reported, the first-in-class dopamine-1 (D1) receptor antagonist reduced the primary endpoint of tic severity scores by 30% compared with placebo among 149 patients in the 12-week, phase 2b D1AMOND trial. 

What was unknown, however, is whether ecopipam would affect the comorbidities of attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder (OCD), and depression that were present in two thirds of participants.

The two key findings in this post hoc analysis were “first, that patients with a nonmotor diagnosis like depression or ADHD did not do any worse in terms of tic efficacy; and second, we didn’t find any evidence that any of the nonmotor symptoms of Tourette’s got worse with ecopipam,” said study investigator Donald Gilbert, MD, professor of pediatrics and neurology at University of Cincinnati Children’s Hospital Medical Center.

Dr. Gilbert presented the results at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024. 
 

No Worsening of ADHD Symptoms

Tourette syndrome affects approximately 1 in 160 children between 5 and 17 years of age in the United States, data from the Tourette Association of America show. Research has shown that 85% of patients with Tourette syndrome will have a co-occurring psychiatric condition. 

Guidelines recommend Comprehensive Behavioral Intervention for Tics (CBIT) as first-line treatment for Tourette syndrome, but cost and access are barriers. The only currently approved medications to treat Tourette syndrome are antipsychotics that act on the D2 receptor, but their use is limited by the potential for weight gain, metabolic changes, drug-induced movement disorders, and risk for suicidality, said Dr. Gilbert. 

The D1AMOND study randomly assigned patients aged 6-17 years with Tourette syndrome and a Yale Global Tic Severity Total Tic Scale score of at least 20 to receive a target steady-state dose of 2 mg/kg/d of oral ecopipam or placebo for a 4-week titration period, followed by an 8-week treatment phase before being tapered off the study drug. 

Patients were allowed to remain on medications without D2-receptor blocking activity for anxiety, OCD, and ADHD if the dosage was stable for 4 weeks before screening and not specifically prescribed for tics. 

A mixed model for repeated measures was used to assess changes in several scales administered at baseline and at weeks 4, 6, 8, and 12: the Swanson, Nolan, and Pelham Teacher and Parent Rating Scale (SNAP-IV); Pediatric Anxiety Rating Scale; Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), and Children’s Depression Rating Scale–Revised (CDRS-R). 

In patients with a co-occurring psychiatric condition, no significant differences were found over time between ecopipam and placebo in terms of SNAP-IV (-4.4; P = .45), Pediatric Anxiety Rating Scale (1.0; P = .62), CDRS-R (-3.2; P = .65), or CY-BOCS (-0.7; P = .76) scores.

For ADHD, the most frequent comorbidity, scores trended lower in the ecopipam group but were not significantly different from those in the placebo group. “We found no evidence that ecopipam worsened ADHD symptoms,” Dr. Gilbert said.
 

No Weight Gain

Suicidal ideation was reported during the dosing period in eight patients in the placebo group and none in the ecopipam group. One patient treated with ecopipam had multiple depressive episodes and dropped out of the study on day 79. Ecopipam was discontinued in another patient because of anxiety. 

Notably, there was more weight gain in the placebo group than in the ecopipam group (2.4 kg vs 1.8 kg) by 12 weeks. No shifts from baseline were seen in blood glucose, A1c, total cholesterol, or triglycerides in either group. 

The lack of weight gain with ecopipam is important, Dr. Gilbert stressed. “Medicines that block D2 so often cause weight gain, and a lot of our patients, unfortunately, can be heavier already,” he explained. “We don’t want to make that worse or put them at a long-term risk of type 2 diabetes.”  

For patients with more severe disease, we really “do need something else besides D2-blockers in our tool kit,” he added. 

Commenting on the study, Tanya Simuni, MD, co-moderator of the session and director of the Parkinson’s Disease and Movement Disorders Center, Northwestern Feinberg School of Medicine, Chicago, said the aim of assessing D1-directed medications is to reduce the negative impact of traditional antipsychotics with a theoretical benefit on hyperkinetic movement.

But the most important thing that they’ve shown is that “there was no negative effect, no liability for the nonmotor manifestations of Tourette’s. That is important because Tourette’s is not a pure motor syndrome, and psychiatric manifestations in a lot of cases are associated with more disease-related quality of life impairment compared to the motor manifestations,” said Dr. Simuni.

That said, she noted, the “ideal drug would be the one that would have benefit for both motor and nonmotor domains.” 
 

Multiple Agents in the Pipeline 

“The neuropharmacology of Tourette syndrome has long remained stagnant, and most existing treatments often fail to balance efficacy with tolerability, underscoring the urgent need for newer therapeutics,” Christos Ganos, MD, professor of neurology, University of Toronto, said in a press release.

He noted that three studies have been published on ecopipam since 2014: an 8-week, open-label trial in adults with Tourette syndrome, a 4-week, placebo-controlled crossover trial in 38 children with Tourette syndrome, and the 12-week D1AMOND trial.

“These studies demonstrated clinically meaningful reductions in tics, without relevant safety concerns or changes in Tourette syndrome-typical neuropsychiatric measures, as also shown by the abstract highlighted here,” Dr. Ganos said. 

“This emerging body of research provides a solid foundation for introducing ecopipam as a novel pharmacological agent to treat tics and may motivate further work, both on the pathophysiology and pharmacotherapy of tic disorders and their associations.”

A single-arm, phase 3 trial is currently underway at 58 centers in North America and Europe investigating the long-term safety and tolerability of ecopipam over 24 months in 150 children, adolescents, and adults with Tourette syndrome. The study is expected to be completed in 2027.

Several other new medications are also under investigation including the vesicular monoamine transporter (VMAT2) inhibitors tetrabenazine, deutetrabenazine, and valbenazine; the PEDE10A inhibitor gemlapodect; the allopregnanolone antagonist sepranolone; and SCI-110, which combines dronabinol (the synthetic form of tetrahydrocannabinol) and the endocannabinoid palmitoylethanolamide.

The study was funded by Emalex Biosciences. Dr. Gilbert’s institution received research support from Emalex Biosciences and PTC Therapeutics. Dr. Gilbert has received publishing royalties from a healthcare-related publication; compensation for serving as a medical expert with Teladoc; Advanced Medical; and the National Vaccine Injury Compensation Program, US Department of Health and Human Services. Simuni reports no relevant conflicts of interest. Dr. Ganos has received honoraria for educational activities from the Movement Disorder Society and academic research support from VolkswagenStiftung. 
 

A version of this article first appeared on Medscape.com.

PHILADELPHIA — The investigational agent ecopipam reduces tic severity in children and adolescents with Tourette syndrome without exacerbating common psychiatric comorbidities, results of a new analysis suggest.

As previously reported, the first-in-class dopamine-1 (D1) receptor antagonist reduced the primary endpoint of tic severity scores by 30% compared with placebo among 149 patients in the 12-week, phase 2b D1AMOND trial. 

What was unknown, however, is whether ecopipam would affect the comorbidities of attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder (OCD), and depression that were present in two thirds of participants.

The two key findings in this post hoc analysis were “first, that patients with a nonmotor diagnosis like depression or ADHD did not do any worse in terms of tic efficacy; and second, we didn’t find any evidence that any of the nonmotor symptoms of Tourette’s got worse with ecopipam,” said study investigator Donald Gilbert, MD, professor of pediatrics and neurology at University of Cincinnati Children’s Hospital Medical Center.

Dr. Gilbert presented the results at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024. 
 

No Worsening of ADHD Symptoms

Tourette syndrome affects approximately 1 in 160 children between 5 and 17 years of age in the United States, data from the Tourette Association of America show. Research has shown that 85% of patients with Tourette syndrome will have a co-occurring psychiatric condition. 

Guidelines recommend Comprehensive Behavioral Intervention for Tics (CBIT) as first-line treatment for Tourette syndrome, but cost and access are barriers. The only currently approved medications to treat Tourette syndrome are antipsychotics that act on the D2 receptor, but their use is limited by the potential for weight gain, metabolic changes, drug-induced movement disorders, and risk for suicidality, said Dr. Gilbert. 

The D1AMOND study randomly assigned patients aged 6-17 years with Tourette syndrome and a Yale Global Tic Severity Total Tic Scale score of at least 20 to receive a target steady-state dose of 2 mg/kg/d of oral ecopipam or placebo for a 4-week titration period, followed by an 8-week treatment phase before being tapered off the study drug. 

Patients were allowed to remain on medications without D2-receptor blocking activity for anxiety, OCD, and ADHD if the dosage was stable for 4 weeks before screening and not specifically prescribed for tics. 

A mixed model for repeated measures was used to assess changes in several scales administered at baseline and at weeks 4, 6, 8, and 12: the Swanson, Nolan, and Pelham Teacher and Parent Rating Scale (SNAP-IV); Pediatric Anxiety Rating Scale; Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), and Children’s Depression Rating Scale–Revised (CDRS-R). 

In patients with a co-occurring psychiatric condition, no significant differences were found over time between ecopipam and placebo in terms of SNAP-IV (-4.4; P = .45), Pediatric Anxiety Rating Scale (1.0; P = .62), CDRS-R (-3.2; P = .65), or CY-BOCS (-0.7; P = .76) scores.

For ADHD, the most frequent comorbidity, scores trended lower in the ecopipam group but were not significantly different from those in the placebo group. “We found no evidence that ecopipam worsened ADHD symptoms,” Dr. Gilbert said.
 

No Weight Gain

Suicidal ideation was reported during the dosing period in eight patients in the placebo group and none in the ecopipam group. One patient treated with ecopipam had multiple depressive episodes and dropped out of the study on day 79. Ecopipam was discontinued in another patient because of anxiety. 

Notably, there was more weight gain in the placebo group than in the ecopipam group (2.4 kg vs 1.8 kg) by 12 weeks. No shifts from baseline were seen in blood glucose, A1c, total cholesterol, or triglycerides in either group. 

The lack of weight gain with ecopipam is important, Dr. Gilbert stressed. “Medicines that block D2 so often cause weight gain, and a lot of our patients, unfortunately, can be heavier already,” he explained. “We don’t want to make that worse or put them at a long-term risk of type 2 diabetes.”  

For patients with more severe disease, we really “do need something else besides D2-blockers in our tool kit,” he added. 

Commenting on the study, Tanya Simuni, MD, co-moderator of the session and director of the Parkinson’s Disease and Movement Disorders Center, Northwestern Feinberg School of Medicine, Chicago, said the aim of assessing D1-directed medications is to reduce the negative impact of traditional antipsychotics with a theoretical benefit on hyperkinetic movement.

But the most important thing that they’ve shown is that “there was no negative effect, no liability for the nonmotor manifestations of Tourette’s. That is important because Tourette’s is not a pure motor syndrome, and psychiatric manifestations in a lot of cases are associated with more disease-related quality of life impairment compared to the motor manifestations,” said Dr. Simuni.

That said, she noted, the “ideal drug would be the one that would have benefit for both motor and nonmotor domains.” 
 

Multiple Agents in the Pipeline 

“The neuropharmacology of Tourette syndrome has long remained stagnant, and most existing treatments often fail to balance efficacy with tolerability, underscoring the urgent need for newer therapeutics,” Christos Ganos, MD, professor of neurology, University of Toronto, said in a press release.

He noted that three studies have been published on ecopipam since 2014: an 8-week, open-label trial in adults with Tourette syndrome, a 4-week, placebo-controlled crossover trial in 38 children with Tourette syndrome, and the 12-week D1AMOND trial.

“These studies demonstrated clinically meaningful reductions in tics, without relevant safety concerns or changes in Tourette syndrome-typical neuropsychiatric measures, as also shown by the abstract highlighted here,” Dr. Ganos said. 

“This emerging body of research provides a solid foundation for introducing ecopipam as a novel pharmacological agent to treat tics and may motivate further work, both on the pathophysiology and pharmacotherapy of tic disorders and their associations.”

A single-arm, phase 3 trial is currently underway at 58 centers in North America and Europe investigating the long-term safety and tolerability of ecopipam over 24 months in 150 children, adolescents, and adults with Tourette syndrome. The study is expected to be completed in 2027.

Several other new medications are also under investigation including the vesicular monoamine transporter (VMAT2) inhibitors tetrabenazine, deutetrabenazine, and valbenazine; the PEDE10A inhibitor gemlapodect; the allopregnanolone antagonist sepranolone; and SCI-110, which combines dronabinol (the synthetic form of tetrahydrocannabinol) and the endocannabinoid palmitoylethanolamide.

The study was funded by Emalex Biosciences. Dr. Gilbert’s institution received research support from Emalex Biosciences and PTC Therapeutics. Dr. Gilbert has received publishing royalties from a healthcare-related publication; compensation for serving as a medical expert with Teladoc; Advanced Medical; and the National Vaccine Injury Compensation Program, US Department of Health and Human Services. Simuni reports no relevant conflicts of interest. Dr. Ganos has received honoraria for educational activities from the Movement Disorder Society and academic research support from VolkswagenStiftung. 
 

A version of this article first appeared on Medscape.com.

MADRID — Individuals with type 2 diabetes and/or obesity plus one or more metabolic risk factors are at a higher risk for metabolic dysfunction–associated steatotic liver disease (MASLD) with fibrosis and progression to more severe liver disease, stated new European guidelines that provide recommendations for diagnosis and management.

“The availability of improved treatment options underlines the need to identify at-risk individuals with MASLD early, as we now possess the tools to positively influence the course of the diseases, which is expected to prevent relevant clinical events,” stated the clinical practice guidelines, updated for the first time since 2016.

“Now we have guidelines that tell clinicians how to monitor the liver,” said Amalia Gastaldelli, PhD, research director at the Institute of Clinical Physiology of the National Research Council in Pisa, Italy, and a member of the panel that developed the guidelines.

Dr. Gastaldelli moderated a session focused on the guidelines at the annual meeting of the European Association for the Study of Diabetes (EASD). In an interview after the session, Dr. Gastaldelli, who leads a cardiometabolic risk research group, stressed the importance of the liver’s role in the body and the need for diabetes specialists to start paying more attention to this vital organ.

“It’s an important organ for monitoring because liver disease is silent, and the patient doesn’t feel unwell until disease is severe,” she said. “Diabetologists already monitor the eye, the heart, the kidney, and so on, but the liver is often neglected,” she said. A 2024 study found that the global pooled prevalence of MASLD among patients with type 2 diabetes was 65.33%.

Dr. Gastaldelli noted the importance of liver status in diabetes care. The liver makes triglycerides and very-low-density lipoprotein cholesterol, which are all major risk factors for atherosclerosis and cardiovascular disease (CVD), she said, as well as producing glucose, which in excess can lead to hyperglycemia.

The guidelines were jointly written by EASD, the European Association for the Study of the Liver, and the European Association for the Study of Obesity, and published in Diabetologia, The Journal of Hepatology, and Obesity Facts.
 

A Metabolic Condition

In the EASD meeting session, Dr. Gastaldelli discussed the reasons for, and implications of, shifting the name from nonalcoholic fatty liver disease (NAFLD) to MASLD.

“The name change focuses on the fact that this is a metabolic disease, while NAFLD had no mention of this and was considered stigmatizing by patients, especially in relation to the words ‘fatty’ and ‘nonalcoholic,’” she said.

According to the guidelines, MASLD is defined as liver steatosis in the presence of one or more cardiometabolic risk factor(s) and the absence of excess alcohol intake.

MASLD has become the most common chronic liver disease and includes isolated steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), MASH-related fibrosis, and cirrhosis.

In the overarching group of steatotic liver disease, a totally new intermediate category has been added: MASLD with moderate (increased) alcohol intake (MetALD), which represents MASLD in people who consume greater amounts of alcohol per week (140-350 g/week and 210-420 g/week for women and men, respectively).

The change in the nomenclature has been incremental and regional, Dr. Gastaldelli said. “The definition first changed from NAFLD to MAFLD, which recognizes the importance of metabolism in the pathophysiology of this disease but does not take into account alcohol intake. MAFLD is still used in Asia, Australasia, and North Africa, while Europe and the Americas have endorsed MASLD.”
 

Case-Finding and Diagnosis

Identifying MASLD cases in people at risk remains incidental, largely because it is a silent disease and is symptom-free until it becomes severe, said Dr. Gastaldelli.

The guideline recognizes that individuals with type 2 diabetes or obesity with additional metabolic risk factor(s) are at a higher risk for MASLD with fibrosis and progression to MASH.

Assessment strategies for severe liver fibrosis in MASLD include the use of noninvasive tests in people who have cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes or obesity or in the presence of one or more metabolic risk factors.

Dr. Gastaldelli noted that type 2 diabetes, metabolic syndrome, and obesity, including abdominal obesity identified by large waist circumference, are the major risk factors and should be warning signs.

“We need to consider abdominal obesity too — we’ve published data in relatively lean people, body mass index < 25, with MASH but without diabetes. Most of the patients accumulated fat viscerally and in the liver and had hypertriglyceridemia and hypercholesterolemia,” she said.

“The guidelines reflect this because the definition of MASLD includes steatosis plus at least one metabolic factor — waist circumference, for example, which is related to visceral fat, hyperlipidemia, or hyperglycemia. Of note, in both pharmacological and diet-induced weight loss, the decrease in liver fat was associated with the decrease in visceral fat.” 

The noninvasive biomarker test, Fibrosis-4 (FIB-4) may be used to assess the risk for liver fibrosis. The FIB-4 index is calculated using a patient’s age and results of three blood tests — aspartate aminotransferase, alanine aminotransferase, and platelet count.

Advanced fibrosis (grade F3-F4) “is a major risk factor for severe outcomes,” said Dr. Gastaldelli. A FIB-4 test result below 1.3 indicates low risk for advanced liver fibrosis, 1.30-2.67 indicates intermediate risk, and above 2.67 indicates high risk.

“When fibrosis increases, then liver enzymes increase and the platelets decrease,” said Dr. Gastaldelli. “It is not a perfect tool, and we need to add in age because at a young age, it is prone to false negatives and when very old — false positives. It’s important to take a global view, especially if the patient has persistent high liver enzymes, but FIB-4 is low.” 

“And if they have more than one metabolic risk factor, proceed with more tests, for example, transient elastography,” she advised. Imaging techniques such as transient elastography may rule out or rule in advanced fibrosis, which is predictive of liver-related outcomes.

“However, imaging techniques only diagnose steatosis and fibrosis, and right now, MASH can only be diagnosed with liver biopsy because we do not have any markers of liver inflammation and ballooning. In the future, noninvasive tests based on imaging and blood tests will be used to identify patients with MASH,” she added.
 

Management of MASLD — Lifestyle and Treatment

“Pharmacological treatments are designed for [patients] with MASH and fibrosis grade F2 or F3, but not MASLD,” Dr. Gastaldelli said. As such, lifestyle interventions are the mainstay of management — including weight loss, dietary changes, physical exercise, and low to no alcohol consumption. “Eating good-quality food and reducing calories are both important because the metabolism responds differently to different nutrients,” Dr. Gastaldelli said.

“In particular, the guidelines advise dietary management because some foods carry liver toxicity, for example, sugary foods with sucrose/fructose especially,” she said, adding that, “complex carbohydrates are less harmful than refined carbohydrates. Processed foods should be avoided if possible because they contain sugars, [as well as] saturated fats and hydrogenated fat, which is particularly bad for the liver. Olive oil is better than butter or margarine, which are rich in saturated fat, and fish and white meat are preferable.”

She added that a diet to help manage type 2 diabetes was not so dissimilar because sugar again needs to be reduced. 

If a patient has severe obesity (and MASLD), data show that bariatric surgery is beneficial. “It not only helps weight loss, but it improves liver histology and has been shown to improve or resolve type 2 diabetes and reduce CVD risk. Importantly, regarding fibrosis, nutritional management after the bariatric surgery is the most important thing,” said Dr. Gastaldelli.

Optimal management of comorbidities — including the use of incretin-based therapies such as semaglutide or tirzepatide for type 2 diabetes or obesity, if indicated — is advised, according to the guidelines.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been shown to have a beneficial effect on MASH, said Dr. Gastaldelli. “They have not shown effectiveness in the resolution of fibrosis, but this might take longer to manifest. However, if the medication is started early enough, it may prevent severe fibrosis. Significant weight loss, both with lifestyle and pharmacological treatment, should lead to an improvement in the liver too.”

There are currently no drugs available in Europe for the treatment of noncirrhotic MASH and severe fibrosis (stage ≥ 2). Resmetirom is the first approved MASH-targeted treatment in noncirrhotic MASH and significant liver fibrosis, with histological effectiveness on steatohepatitis and fibrosis, together with an acceptable safety and tolerability profile, but, for the moment, this agent is only available in United States.

Finally, turning to MASH-related cirrhosis, the guidelines advise adaptations of metabolic drugs, nutritional counseling, and surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.

After the session, this news organization spoke to Tushy Kailayanathan, MBBS BSc, medical director of the liver MRI company, Perspectum, who reviewed the limitations of the FIB-4 test. The FIB-4 test identifies those with advanced fibrosis in the liver, for example, patients with hepatitis C, she noted; however, “it performs worse in type 2 diabetic patients and in the elderly. There is little clinical guidance on the adjustment of FIB-4 thresholds needed for these high cardiometabolic risk groups. The priority patients are missed by FIB-4 because those individuals with early and active disease may not yet have progressed to advanced disease detected by FIB-4.”

These individuals are exactly those amenable to primary care prevention strategies, said Dr. Kailayanathan. Because of the nature of early and active liver disease in patients with high cardiometabolic risk, it would make sense to shift some diagnostic protocols into primary care.

“These individuals are exactly those amenable to primary care prevention strategies at annual diabetic review because they are likely to have modifiable cardiometabolic risk factors such as metabolic syndrome and would benefit from lifestyle and therapeutic intervention, including GLP-1 RAs and SGLT2is [sodium-glucose cotransporter-2 inhibitors],” she said. “Case-finding and detection of early-stage MASLD is a priority in diabetics, and there is an unmet need for accurate biomarkers to measure liver fat and inflammation early.”

Dr. Gastaldelli has been on the advisory board or consulting for Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Fractyl, Pfizer, Merck-MSD, MetaDeq and a speaker for Eli Lilly, Novo Nordisk, and Pfizer. Dr. Kailayanathan is medical director at Perspectum, a UK-based company involved in liver imaging technology.

A version of this article first appeared on Medscape.com.

MADRID — Individuals with type 2 diabetes and/or obesity plus one or more metabolic risk factors are at a higher risk for metabolic dysfunction–associated steatotic liver disease (MASLD) with fibrosis and progression to more severe liver disease, stated new European guidelines that provide recommendations for diagnosis and management.

“The availability of improved treatment options underlines the need to identify at-risk individuals with MASLD early, as we now possess the tools to positively influence the course of the diseases, which is expected to prevent relevant clinical events,” stated the clinical practice guidelines, updated for the first time since 2016.

“Now we have guidelines that tell clinicians how to monitor the liver,” said Amalia Gastaldelli, PhD, research director at the Institute of Clinical Physiology of the National Research Council in Pisa, Italy, and a member of the panel that developed the guidelines.

Dr. Gastaldelli moderated a session focused on the guidelines at the annual meeting of the European Association for the Study of Diabetes (EASD). In an interview after the session, Dr. Gastaldelli, who leads a cardiometabolic risk research group, stressed the importance of the liver’s role in the body and the need for diabetes specialists to start paying more attention to this vital organ.

“It’s an important organ for monitoring because liver disease is silent, and the patient doesn’t feel unwell until disease is severe,” she said. “Diabetologists already monitor the eye, the heart, the kidney, and so on, but the liver is often neglected,” she said. A 2024 study found that the global pooled prevalence of MASLD among patients with type 2 diabetes was 65.33%.

Dr. Gastaldelli noted the importance of liver status in diabetes care. The liver makes triglycerides and very-low-density lipoprotein cholesterol, which are all major risk factors for atherosclerosis and cardiovascular disease (CVD), she said, as well as producing glucose, which in excess can lead to hyperglycemia.

The guidelines were jointly written by EASD, the European Association for the Study of the Liver, and the European Association for the Study of Obesity, and published in Diabetologia, The Journal of Hepatology, and Obesity Facts.
 

A Metabolic Condition

In the EASD meeting session, Dr. Gastaldelli discussed the reasons for, and implications of, shifting the name from nonalcoholic fatty liver disease (NAFLD) to MASLD.

“The name change focuses on the fact that this is a metabolic disease, while NAFLD had no mention of this and was considered stigmatizing by patients, especially in relation to the words ‘fatty’ and ‘nonalcoholic,’” she said.

According to the guidelines, MASLD is defined as liver steatosis in the presence of one or more cardiometabolic risk factor(s) and the absence of excess alcohol intake.

MASLD has become the most common chronic liver disease and includes isolated steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), MASH-related fibrosis, and cirrhosis.

In the overarching group of steatotic liver disease, a totally new intermediate category has been added: MASLD with moderate (increased) alcohol intake (MetALD), which represents MASLD in people who consume greater amounts of alcohol per week (140-350 g/week and 210-420 g/week for women and men, respectively).

The change in the nomenclature has been incremental and regional, Dr. Gastaldelli said. “The definition first changed from NAFLD to MAFLD, which recognizes the importance of metabolism in the pathophysiology of this disease but does not take into account alcohol intake. MAFLD is still used in Asia, Australasia, and North Africa, while Europe and the Americas have endorsed MASLD.”
 

Case-Finding and Diagnosis

Identifying MASLD cases in people at risk remains incidental, largely because it is a silent disease and is symptom-free until it becomes severe, said Dr. Gastaldelli.

The guideline recognizes that individuals with type 2 diabetes or obesity with additional metabolic risk factor(s) are at a higher risk for MASLD with fibrosis and progression to MASH.

Assessment strategies for severe liver fibrosis in MASLD include the use of noninvasive tests in people who have cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes or obesity or in the presence of one or more metabolic risk factors.

Dr. Gastaldelli noted that type 2 diabetes, metabolic syndrome, and obesity, including abdominal obesity identified by large waist circumference, are the major risk factors and should be warning signs.

“We need to consider abdominal obesity too — we’ve published data in relatively lean people, body mass index < 25, with MASH but without diabetes. Most of the patients accumulated fat viscerally and in the liver and had hypertriglyceridemia and hypercholesterolemia,” she said.

“The guidelines reflect this because the definition of MASLD includes steatosis plus at least one metabolic factor — waist circumference, for example, which is related to visceral fat, hyperlipidemia, or hyperglycemia. Of note, in both pharmacological and diet-induced weight loss, the decrease in liver fat was associated with the decrease in visceral fat.” 

The noninvasive biomarker test, Fibrosis-4 (FIB-4) may be used to assess the risk for liver fibrosis. The FIB-4 index is calculated using a patient’s age and results of three blood tests — aspartate aminotransferase, alanine aminotransferase, and platelet count.

Advanced fibrosis (grade F3-F4) “is a major risk factor for severe outcomes,” said Dr. Gastaldelli. A FIB-4 test result below 1.3 indicates low risk for advanced liver fibrosis, 1.30-2.67 indicates intermediate risk, and above 2.67 indicates high risk.

“When fibrosis increases, then liver enzymes increase and the platelets decrease,” said Dr. Gastaldelli. “It is not a perfect tool, and we need to add in age because at a young age, it is prone to false negatives and when very old — false positives. It’s important to take a global view, especially if the patient has persistent high liver enzymes, but FIB-4 is low.” 

“And if they have more than one metabolic risk factor, proceed with more tests, for example, transient elastography,” she advised. Imaging techniques such as transient elastography may rule out or rule in advanced fibrosis, which is predictive of liver-related outcomes.

“However, imaging techniques only diagnose steatosis and fibrosis, and right now, MASH can only be diagnosed with liver biopsy because we do not have any markers of liver inflammation and ballooning. In the future, noninvasive tests based on imaging and blood tests will be used to identify patients with MASH,” she added.
 

Management of MASLD — Lifestyle and Treatment

“Pharmacological treatments are designed for [patients] with MASH and fibrosis grade F2 or F3, but not MASLD,” Dr. Gastaldelli said. As such, lifestyle interventions are the mainstay of management — including weight loss, dietary changes, physical exercise, and low to no alcohol consumption. “Eating good-quality food and reducing calories are both important because the metabolism responds differently to different nutrients,” Dr. Gastaldelli said.

“In particular, the guidelines advise dietary management because some foods carry liver toxicity, for example, sugary foods with sucrose/fructose especially,” she said, adding that, “complex carbohydrates are less harmful than refined carbohydrates. Processed foods should be avoided if possible because they contain sugars, [as well as] saturated fats and hydrogenated fat, which is particularly bad for the liver. Olive oil is better than butter or margarine, which are rich in saturated fat, and fish and white meat are preferable.”

She added that a diet to help manage type 2 diabetes was not so dissimilar because sugar again needs to be reduced. 

If a patient has severe obesity (and MASLD), data show that bariatric surgery is beneficial. “It not only helps weight loss, but it improves liver histology and has been shown to improve or resolve type 2 diabetes and reduce CVD risk. Importantly, regarding fibrosis, nutritional management after the bariatric surgery is the most important thing,” said Dr. Gastaldelli.

Optimal management of comorbidities — including the use of incretin-based therapies such as semaglutide or tirzepatide for type 2 diabetes or obesity, if indicated — is advised, according to the guidelines.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been shown to have a beneficial effect on MASH, said Dr. Gastaldelli. “They have not shown effectiveness in the resolution of fibrosis, but this might take longer to manifest. However, if the medication is started early enough, it may prevent severe fibrosis. Significant weight loss, both with lifestyle and pharmacological treatment, should lead to an improvement in the liver too.”

There are currently no drugs available in Europe for the treatment of noncirrhotic MASH and severe fibrosis (stage ≥ 2). Resmetirom is the first approved MASH-targeted treatment in noncirrhotic MASH and significant liver fibrosis, with histological effectiveness on steatohepatitis and fibrosis, together with an acceptable safety and tolerability profile, but, for the moment, this agent is only available in United States.

Finally, turning to MASH-related cirrhosis, the guidelines advise adaptations of metabolic drugs, nutritional counseling, and surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.

After the session, this news organization spoke to Tushy Kailayanathan, MBBS BSc, medical director of the liver MRI company, Perspectum, who reviewed the limitations of the FIB-4 test. The FIB-4 test identifies those with advanced fibrosis in the liver, for example, patients with hepatitis C, she noted; however, “it performs worse in type 2 diabetic patients and in the elderly. There is little clinical guidance on the adjustment of FIB-4 thresholds needed for these high cardiometabolic risk groups. The priority patients are missed by FIB-4 because those individuals with early and active disease may not yet have progressed to advanced disease detected by FIB-4.”

These individuals are exactly those amenable to primary care prevention strategies, said Dr. Kailayanathan. Because of the nature of early and active liver disease in patients with high cardiometabolic risk, it would make sense to shift some diagnostic protocols into primary care.

“These individuals are exactly those amenable to primary care prevention strategies at annual diabetic review because they are likely to have modifiable cardiometabolic risk factors such as metabolic syndrome and would benefit from lifestyle and therapeutic intervention, including GLP-1 RAs and SGLT2is [sodium-glucose cotransporter-2 inhibitors],” she said. “Case-finding and detection of early-stage MASLD is a priority in diabetics, and there is an unmet need for accurate biomarkers to measure liver fat and inflammation early.”

Dr. Gastaldelli has been on the advisory board or consulting for Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Fractyl, Pfizer, Merck-MSD, MetaDeq and a speaker for Eli Lilly, Novo Nordisk, and Pfizer. Dr. Kailayanathan is medical director at Perspectum, a UK-based company involved in liver imaging technology.

A version of this article first appeared on Medscape.com.

MADRID — Individuals with type 2 diabetes and/or obesity plus one or more metabolic risk factors are at a higher risk for metabolic dysfunction–associated steatotic liver disease (MASLD) with fibrosis and progression to more severe liver disease, stated new European guidelines that provide recommendations for diagnosis and management.

“The availability of improved treatment options underlines the need to identify at-risk individuals with MASLD early, as we now possess the tools to positively influence the course of the diseases, which is expected to prevent relevant clinical events,” stated the clinical practice guidelines, updated for the first time since 2016.

“Now we have guidelines that tell clinicians how to monitor the liver,” said Amalia Gastaldelli, PhD, research director at the Institute of Clinical Physiology of the National Research Council in Pisa, Italy, and a member of the panel that developed the guidelines.

Dr. Gastaldelli moderated a session focused on the guidelines at the annual meeting of the European Association for the Study of Diabetes (EASD). In an interview after the session, Dr. Gastaldelli, who leads a cardiometabolic risk research group, stressed the importance of the liver’s role in the body and the need for diabetes specialists to start paying more attention to this vital organ.

“It’s an important organ for monitoring because liver disease is silent, and the patient doesn’t feel unwell until disease is severe,” she said. “Diabetologists already monitor the eye, the heart, the kidney, and so on, but the liver is often neglected,” she said. A 2024 study found that the global pooled prevalence of MASLD among patients with type 2 diabetes was 65.33%.

Dr. Gastaldelli noted the importance of liver status in diabetes care. The liver makes triglycerides and very-low-density lipoprotein cholesterol, which are all major risk factors for atherosclerosis and cardiovascular disease (CVD), she said, as well as producing glucose, which in excess can lead to hyperglycemia.

The guidelines were jointly written by EASD, the European Association for the Study of the Liver, and the European Association for the Study of Obesity, and published in Diabetologia, The Journal of Hepatology, and Obesity Facts.
 

A Metabolic Condition

In the EASD meeting session, Dr. Gastaldelli discussed the reasons for, and implications of, shifting the name from nonalcoholic fatty liver disease (NAFLD) to MASLD.

“The name change focuses on the fact that this is a metabolic disease, while NAFLD had no mention of this and was considered stigmatizing by patients, especially in relation to the words ‘fatty’ and ‘nonalcoholic,’” she said.

According to the guidelines, MASLD is defined as liver steatosis in the presence of one or more cardiometabolic risk factor(s) and the absence of excess alcohol intake.

MASLD has become the most common chronic liver disease and includes isolated steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), MASH-related fibrosis, and cirrhosis.

In the overarching group of steatotic liver disease, a totally new intermediate category has been added: MASLD with moderate (increased) alcohol intake (MetALD), which represents MASLD in people who consume greater amounts of alcohol per week (140-350 g/week and 210-420 g/week for women and men, respectively).

The change in the nomenclature has been incremental and regional, Dr. Gastaldelli said. “The definition first changed from NAFLD to MAFLD, which recognizes the importance of metabolism in the pathophysiology of this disease but does not take into account alcohol intake. MAFLD is still used in Asia, Australasia, and North Africa, while Europe and the Americas have endorsed MASLD.”
 

Case-Finding and Diagnosis

Identifying MASLD cases in people at risk remains incidental, largely because it is a silent disease and is symptom-free until it becomes severe, said Dr. Gastaldelli.

The guideline recognizes that individuals with type 2 diabetes or obesity with additional metabolic risk factor(s) are at a higher risk for MASLD with fibrosis and progression to MASH.

Assessment strategies for severe liver fibrosis in MASLD include the use of noninvasive tests in people who have cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes or obesity or in the presence of one or more metabolic risk factors.

Dr. Gastaldelli noted that type 2 diabetes, metabolic syndrome, and obesity, including abdominal obesity identified by large waist circumference, are the major risk factors and should be warning signs.

“We need to consider abdominal obesity too — we’ve published data in relatively lean people, body mass index < 25, with MASH but without diabetes. Most of the patients accumulated fat viscerally and in the liver and had hypertriglyceridemia and hypercholesterolemia,” she said.

“The guidelines reflect this because the definition of MASLD includes steatosis plus at least one metabolic factor — waist circumference, for example, which is related to visceral fat, hyperlipidemia, or hyperglycemia. Of note, in both pharmacological and diet-induced weight loss, the decrease in liver fat was associated with the decrease in visceral fat.” 

The noninvasive biomarker test, Fibrosis-4 (FIB-4) may be used to assess the risk for liver fibrosis. The FIB-4 index is calculated using a patient’s age and results of three blood tests — aspartate aminotransferase, alanine aminotransferase, and platelet count.

Advanced fibrosis (grade F3-F4) “is a major risk factor for severe outcomes,” said Dr. Gastaldelli. A FIB-4 test result below 1.3 indicates low risk for advanced liver fibrosis, 1.30-2.67 indicates intermediate risk, and above 2.67 indicates high risk.

“When fibrosis increases, then liver enzymes increase and the platelets decrease,” said Dr. Gastaldelli. “It is not a perfect tool, and we need to add in age because at a young age, it is prone to false negatives and when very old — false positives. It’s important to take a global view, especially if the patient has persistent high liver enzymes, but FIB-4 is low.” 

“And if they have more than one metabolic risk factor, proceed with more tests, for example, transient elastography,” she advised. Imaging techniques such as transient elastography may rule out or rule in advanced fibrosis, which is predictive of liver-related outcomes.

“However, imaging techniques only diagnose steatosis and fibrosis, and right now, MASH can only be diagnosed with liver biopsy because we do not have any markers of liver inflammation and ballooning. In the future, noninvasive tests based on imaging and blood tests will be used to identify patients with MASH,” she added.
 

Management of MASLD — Lifestyle and Treatment

“Pharmacological treatments are designed for [patients] with MASH and fibrosis grade F2 or F3, but not MASLD,” Dr. Gastaldelli said. As such, lifestyle interventions are the mainstay of management — including weight loss, dietary changes, physical exercise, and low to no alcohol consumption. “Eating good-quality food and reducing calories are both important because the metabolism responds differently to different nutrients,” Dr. Gastaldelli said.

“In particular, the guidelines advise dietary management because some foods carry liver toxicity, for example, sugary foods with sucrose/fructose especially,” she said, adding that, “complex carbohydrates are less harmful than refined carbohydrates. Processed foods should be avoided if possible because they contain sugars, [as well as] saturated fats and hydrogenated fat, which is particularly bad for the liver. Olive oil is better than butter or margarine, which are rich in saturated fat, and fish and white meat are preferable.”

She added that a diet to help manage type 2 diabetes was not so dissimilar because sugar again needs to be reduced. 

If a patient has severe obesity (and MASLD), data show that bariatric surgery is beneficial. “It not only helps weight loss, but it improves liver histology and has been shown to improve or resolve type 2 diabetes and reduce CVD risk. Importantly, regarding fibrosis, nutritional management after the bariatric surgery is the most important thing,” said Dr. Gastaldelli.

Optimal management of comorbidities — including the use of incretin-based therapies such as semaglutide or tirzepatide for type 2 diabetes or obesity, if indicated — is advised, according to the guidelines.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been shown to have a beneficial effect on MASH, said Dr. Gastaldelli. “They have not shown effectiveness in the resolution of fibrosis, but this might take longer to manifest. However, if the medication is started early enough, it may prevent severe fibrosis. Significant weight loss, both with lifestyle and pharmacological treatment, should lead to an improvement in the liver too.”

There are currently no drugs available in Europe for the treatment of noncirrhotic MASH and severe fibrosis (stage ≥ 2). Resmetirom is the first approved MASH-targeted treatment in noncirrhotic MASH and significant liver fibrosis, with histological effectiveness on steatohepatitis and fibrosis, together with an acceptable safety and tolerability profile, but, for the moment, this agent is only available in United States.

Finally, turning to MASH-related cirrhosis, the guidelines advise adaptations of metabolic drugs, nutritional counseling, and surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.

After the session, this news organization spoke to Tushy Kailayanathan, MBBS BSc, medical director of the liver MRI company, Perspectum, who reviewed the limitations of the FIB-4 test. The FIB-4 test identifies those with advanced fibrosis in the liver, for example, patients with hepatitis C, she noted; however, “it performs worse in type 2 diabetic patients and in the elderly. There is little clinical guidance on the adjustment of FIB-4 thresholds needed for these high cardiometabolic risk groups. The priority patients are missed by FIB-4 because those individuals with early and active disease may not yet have progressed to advanced disease detected by FIB-4.”

These individuals are exactly those amenable to primary care prevention strategies, said Dr. Kailayanathan. Because of the nature of early and active liver disease in patients with high cardiometabolic risk, it would make sense to shift some diagnostic protocols into primary care.

“These individuals are exactly those amenable to primary care prevention strategies at annual diabetic review because they are likely to have modifiable cardiometabolic risk factors such as metabolic syndrome and would benefit from lifestyle and therapeutic intervention, including GLP-1 RAs and SGLT2is [sodium-glucose cotransporter-2 inhibitors],” she said. “Case-finding and detection of early-stage MASLD is a priority in diabetics, and there is an unmet need for accurate biomarkers to measure liver fat and inflammation early.”

Dr. Gastaldelli has been on the advisory board or consulting for Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Fractyl, Pfizer, Merck-MSD, MetaDeq and a speaker for Eli Lilly, Novo Nordisk, and Pfizer. Dr. Kailayanathan is medical director at Perspectum, a UK-based company involved in liver imaging technology.

A version of this article first appeared on Medscape.com.

A study by researchers at two academic medical centers determined which infertile men may benefit from treatment with anastrozole. They found that those with azoospermia (no sperm in their ejaculate) rarely respond to the drug while those with baseline nonazoospermia, lower levels of luteinizing hormone and follicle-stimulating hormone, and higher levels of testosterone are more likely to obtain improvement in semen parameters.

The retrospective cohort study of 90 infertile men, published in the October 2023 issue of Fertility and Sterility, was conducted by researchers at Cleveland Clinic and the University of California Los Angeles. It is the first project of Male Organ Biology Yielding United Science (MOBYUS), a new, multi-institutional research consortium seeking to better understand male infertility and expand treatment options. 

Launched last year, MOBYUS now includes investigators from 14 large US-based academic medical centers. They select research topics and search their patient population for eligible participants and share resulting deidentified data for analysis and publication. 

Members of the consortium conducted another study which found that combination therapy with clomiphene citrate and anastrozole was associated with modest benefits on semen parameters, including volume, concentration, and motility after treatment, compared with anastrozole monotherapy. That retrospective cohort analysis of 21 men was published online in Translational Andrology and Urology in February. 

“We know that if we treat the right men with these medications, about 40% will improve their fertility, but only if we choose the right population. These studies identified those groups,” Scott Lundy, MD, PhD, section head of male infertility at Cleveland Clinic’s Glickman Urological and Kidney Institute in Cleveland, and director of the clinic’s andrology lab, told Medscape Medical News. 

Dr. Lundy, a coauthor of both papers, conceived MOBYUS to overcome constraints in research into male infertility. Many studies in the field are limited by small numbers of patients and retrospective designs, he said. “I sought to develop a collaborative network of reproductive urologists and hospitals like ours, so that we can combine our data and generate large series of data, even for rare patient groups, so that we can improve their patient outcomes,” he said.

“Our treatments are in the stone age in many ways. We are far behind other types of treatment for other conditions, including female infertility,” Dr. Lundy added. “And so, our goal is to identify new and data-driven ways to help these men become fathers, whether those are medications or surgeries or combinations of treatments.”
 

Moving the Field Forward

The name of the consortium is a cheeky play on Moby Dick, the most famous sperm whale. MOBYUS investigators conveyed the challenges that patients, doctors, and researchers experience in an article published last December in the Journal of Urology. 

They noted that 1 in 6 couples will have difficulty conceiving a child, with male-factor infertility contributing to at least half of such cases. The lead author, Catherine Nam, MD, a principal investigator for MOBYUS at the University of Michigan, in Ann Arbor, said the paper is unusual for a medical journal, as it provides personal accounts of the psychological and emotional aspects of infertility as well as factors that have led to a global decline in sperm counts among men and the financial costs of treatment.

Dr. Nam said infertility is a sensitive topic for couples and families to talk about and there is less conversation about male infertility than female infertility. “I think the only way that we can be able to make headway, both in terms of protocol and policy outcomes, is to really start to raise awareness,” said Dr. Nam, who is doing a fellowship in clinical andrology at Northwestern University, in Chicago.

Dr. Nam said the collaborative environment of MOBYUS has enabled her to learn about different practice patterns across different institutions. “For someone like me just starting off my professional career in male infertility, an opportunity like this is incredibly exciting and makes me very hopeful about the kinds of collaboration and scientific discovery that we’re able to do together as a group,” she said.

Robert E. Brannigan, MD, vice chair of clinical urology at Northwestern University Feinberg School of Medicine, Chicago, said the consortium is drawing on the strength of many individual centers and allowing them to study critical issues in the field. The group’s outstanding clinicians and scientists “are looking to move the field forward, and I applaud them and I’m eager to watch things unfold,” said Dr. Brannigan, who is not a member of the group.

Dr. Brannigan noted that for a large percentage of patients, clinicians cannot identify the root cause of their impaired reproductive potential. Some people may have a recognizable decline in semen parameters over time without clear lifestyle issues or clear hormonal imbalances or anatomical problems. 

“And the question is, what’s causing that? Is there some as yet unrecognized environmental exposure? Is there some underlying genetic issue that’s predisposing to decline in semen parameters over time? We see this, and we don’t have answers,” Dr. Brannigan said. 

“This is where I think the potential power of a large group like MOBYUS comes into play,” he added. “When you’ve got large datasets and very granular information about your patients, sometimes that can provide the opportunity for insights that can then answer the question, ‘What is the root cause of my patient’s challenges?’ ”

Dr. Brannigan was part of a previous group, the Andrology Research Consortium, which collected data on patient history and treatment through a standardized questionnaire. The consortium was founded in 2013 by the Society for the Study of Male Reproduction, a specialty section of the American Urological Association, to obtain data on the demographics, clinical characteristics, and fertility histories and therapies of men referred for a male infertility investigation at clinics across North America. 

Clinicians analyzed data from the questionnaires, which a team in Toronto collected and stored, in a series of studies, including a comparison of fertility characteristics between men in the United States and Canada. Dr. Brannigan said MOBYUS is poised to produce a large dataset that can address retrospective questions and potentially prospectively collect data to answer prospective questions.
 

Clinical Implications

Dr. Lundy said between 100 and 200 practicing reproductive urologists across the country regularly communicate with each other. He first raised the idea of creating a consortium with friends and colleagues and then discussed it at scientific meetings. The network steadily gained traction and is continuing to add institutions. “There’s a great deal of excitement in our community about this,” Dr. Lundy said.

MOBYUS, which is IRB approved, has a database with data from more than 4000 patients. The consortium has not received any industry funding but plans to pursue grant applications in the future. 

The MOBYUS website includes a list of its member institutions and leading investigators and its three proof-of-principle manuscripts published to date. The team identifies new research projects at monthly virtual meetings.

Dr. Lundy said MOBYUS’ main goal is to identify a treatment that will change the avenue available for a couple to get pregnant. For example, he said, if a man has zero sperm in his semen, he often requires surgery to find and remove sperm from the testicle. If medications can produce low sperm counts, sperm found in the ejaculate can be frozen and surgery can be avoided. 

Dr. Lundy said MOBYUS’ two publications on medical therapies have changed clinical practice, as he and many others have begun to provide the treatments on more carefully selected patients with good outcomes. 

Dr. Nam said patients want to know what they can expect from therapies and these research findings will have “a lot of clinical implications” in counseling them. 

The MOBYUS team will be describing the consortium and its goals in an abstract presentation at the American Society for Reproductive Medicine Scientific Congress & Expo, to be held October 19-23 in Denver, Colorado, and in an oral presentation at the Sexual Medicine Society of North America’s annual fall scientific meeting, to be held October 17-20 in Scottsdale, Arizona.

The sources in this story reported no relevant financial conflicts of interest.
 

A version of this article first appeared on Medscape.com.

A study by researchers at two academic medical centers determined which infertile men may benefit from treatment with anastrozole. They found that those with azoospermia (no sperm in their ejaculate) rarely respond to the drug while those with baseline nonazoospermia, lower levels of luteinizing hormone and follicle-stimulating hormone, and higher levels of testosterone are more likely to obtain improvement in semen parameters.

The retrospective cohort study of 90 infertile men, published in the October 2023 issue of Fertility and Sterility, was conducted by researchers at Cleveland Clinic and the University of California Los Angeles. It is the first project of Male Organ Biology Yielding United Science (MOBYUS), a new, multi-institutional research consortium seeking to better understand male infertility and expand treatment options. 

Launched last year, MOBYUS now includes investigators from 14 large US-based academic medical centers. They select research topics and search their patient population for eligible participants and share resulting deidentified data for analysis and publication. 

Members of the consortium conducted another study which found that combination therapy with clomiphene citrate and anastrozole was associated with modest benefits on semen parameters, including volume, concentration, and motility after treatment, compared with anastrozole monotherapy. That retrospective cohort analysis of 21 men was published online in Translational Andrology and Urology in February. 

“We know that if we treat the right men with these medications, about 40% will improve their fertility, but only if we choose the right population. These studies identified those groups,” Scott Lundy, MD, PhD, section head of male infertility at Cleveland Clinic’s Glickman Urological and Kidney Institute in Cleveland, and director of the clinic’s andrology lab, told Medscape Medical News. 

Dr. Lundy, a coauthor of both papers, conceived MOBYUS to overcome constraints in research into male infertility. Many studies in the field are limited by small numbers of patients and retrospective designs, he said. “I sought to develop a collaborative network of reproductive urologists and hospitals like ours, so that we can combine our data and generate large series of data, even for rare patient groups, so that we can improve their patient outcomes,” he said.

“Our treatments are in the stone age in many ways. We are far behind other types of treatment for other conditions, including female infertility,” Dr. Lundy added. “And so, our goal is to identify new and data-driven ways to help these men become fathers, whether those are medications or surgeries or combinations of treatments.”
 

Moving the Field Forward

The name of the consortium is a cheeky play on Moby Dick, the most famous sperm whale. MOBYUS investigators conveyed the challenges that patients, doctors, and researchers experience in an article published last December in the Journal of Urology. 

They noted that 1 in 6 couples will have difficulty conceiving a child, with male-factor infertility contributing to at least half of such cases. The lead author, Catherine Nam, MD, a principal investigator for MOBYUS at the University of Michigan, in Ann Arbor, said the paper is unusual for a medical journal, as it provides personal accounts of the psychological and emotional aspects of infertility as well as factors that have led to a global decline in sperm counts among men and the financial costs of treatment.

Dr. Nam said infertility is a sensitive topic for couples and families to talk about and there is less conversation about male infertility than female infertility. “I think the only way that we can be able to make headway, both in terms of protocol and policy outcomes, is to really start to raise awareness,” said Dr. Nam, who is doing a fellowship in clinical andrology at Northwestern University, in Chicago.

Dr. Nam said the collaborative environment of MOBYUS has enabled her to learn about different practice patterns across different institutions. “For someone like me just starting off my professional career in male infertility, an opportunity like this is incredibly exciting and makes me very hopeful about the kinds of collaboration and scientific discovery that we’re able to do together as a group,” she said.

Robert E. Brannigan, MD, vice chair of clinical urology at Northwestern University Feinberg School of Medicine, Chicago, said the consortium is drawing on the strength of many individual centers and allowing them to study critical issues in the field. The group’s outstanding clinicians and scientists “are looking to move the field forward, and I applaud them and I’m eager to watch things unfold,” said Dr. Brannigan, who is not a member of the group.

Dr. Brannigan noted that for a large percentage of patients, clinicians cannot identify the root cause of their impaired reproductive potential. Some people may have a recognizable decline in semen parameters over time without clear lifestyle issues or clear hormonal imbalances or anatomical problems. 

“And the question is, what’s causing that? Is there some as yet unrecognized environmental exposure? Is there some underlying genetic issue that’s predisposing to decline in semen parameters over time? We see this, and we don’t have answers,” Dr. Brannigan said. 

“This is where I think the potential power of a large group like MOBYUS comes into play,” he added. “When you’ve got large datasets and very granular information about your patients, sometimes that can provide the opportunity for insights that can then answer the question, ‘What is the root cause of my patient’s challenges?’ ”

Dr. Brannigan was part of a previous group, the Andrology Research Consortium, which collected data on patient history and treatment through a standardized questionnaire. The consortium was founded in 2013 by the Society for the Study of Male Reproduction, a specialty section of the American Urological Association, to obtain data on the demographics, clinical characteristics, and fertility histories and therapies of men referred for a male infertility investigation at clinics across North America. 

Clinicians analyzed data from the questionnaires, which a team in Toronto collected and stored, in a series of studies, including a comparison of fertility characteristics between men in the United States and Canada. Dr. Brannigan said MOBYUS is poised to produce a large dataset that can address retrospective questions and potentially prospectively collect data to answer prospective questions.
 

Clinical Implications

Dr. Lundy said between 100 and 200 practicing reproductive urologists across the country regularly communicate with each other. He first raised the idea of creating a consortium with friends and colleagues and then discussed it at scientific meetings. The network steadily gained traction and is continuing to add institutions. “There’s a great deal of excitement in our community about this,” Dr. Lundy said.

MOBYUS, which is IRB approved, has a database with data from more than 4000 patients. The consortium has not received any industry funding but plans to pursue grant applications in the future. 

The MOBYUS website includes a list of its member institutions and leading investigators and its three proof-of-principle manuscripts published to date. The team identifies new research projects at monthly virtual meetings.

Dr. Lundy said MOBYUS’ main goal is to identify a treatment that will change the avenue available for a couple to get pregnant. For example, he said, if a man has zero sperm in his semen, he often requires surgery to find and remove sperm from the testicle. If medications can produce low sperm counts, sperm found in the ejaculate can be frozen and surgery can be avoided. 

Dr. Lundy said MOBYUS’ two publications on medical therapies have changed clinical practice, as he and many others have begun to provide the treatments on more carefully selected patients with good outcomes. 

Dr. Nam said patients want to know what they can expect from therapies and these research findings will have “a lot of clinical implications” in counseling them. 

The MOBYUS team will be describing the consortium and its goals in an abstract presentation at the American Society for Reproductive Medicine Scientific Congress & Expo, to be held October 19-23 in Denver, Colorado, and in an oral presentation at the Sexual Medicine Society of North America’s annual fall scientific meeting, to be held October 17-20 in Scottsdale, Arizona.

The sources in this story reported no relevant financial conflicts of interest.
 

A version of this article first appeared on Medscape.com.

A study by researchers at two academic medical centers determined which infertile men may benefit from treatment with anastrozole. They found that those with azoospermia (no sperm in their ejaculate) rarely respond to the drug while those with baseline nonazoospermia, lower levels of luteinizing hormone and follicle-stimulating hormone, and higher levels of testosterone are more likely to obtain improvement in semen parameters.

The retrospective cohort study of 90 infertile men, published in the October 2023 issue of Fertility and Sterility, was conducted by researchers at Cleveland Clinic and the University of California Los Angeles. It is the first project of Male Organ Biology Yielding United Science (MOBYUS), a new, multi-institutional research consortium seeking to better understand male infertility and expand treatment options. 

Launched last year, MOBYUS now includes investigators from 14 large US-based academic medical centers. They select research topics and search their patient population for eligible participants and share resulting deidentified data for analysis and publication. 

Members of the consortium conducted another study which found that combination therapy with clomiphene citrate and anastrozole was associated with modest benefits on semen parameters, including volume, concentration, and motility after treatment, compared with anastrozole monotherapy. That retrospective cohort analysis of 21 men was published online in Translational Andrology and Urology in February. 

“We know that if we treat the right men with these medications, about 40% will improve their fertility, but only if we choose the right population. These studies identified those groups,” Scott Lundy, MD, PhD, section head of male infertility at Cleveland Clinic’s Glickman Urological and Kidney Institute in Cleveland, and director of the clinic’s andrology lab, told Medscape Medical News. 

Dr. Lundy, a coauthor of both papers, conceived MOBYUS to overcome constraints in research into male infertility. Many studies in the field are limited by small numbers of patients and retrospective designs, he said. “I sought to develop a collaborative network of reproductive urologists and hospitals like ours, so that we can combine our data and generate large series of data, even for rare patient groups, so that we can improve their patient outcomes,” he said.

“Our treatments are in the stone age in many ways. We are far behind other types of treatment for other conditions, including female infertility,” Dr. Lundy added. “And so, our goal is to identify new and data-driven ways to help these men become fathers, whether those are medications or surgeries or combinations of treatments.”
 

Moving the Field Forward

The name of the consortium is a cheeky play on Moby Dick, the most famous sperm whale. MOBYUS investigators conveyed the challenges that patients, doctors, and researchers experience in an article published last December in the Journal of Urology. 

They noted that 1 in 6 couples will have difficulty conceiving a child, with male-factor infertility contributing to at least half of such cases. The lead author, Catherine Nam, MD, a principal investigator for MOBYUS at the University of Michigan, in Ann Arbor, said the paper is unusual for a medical journal, as it provides personal accounts of the psychological and emotional aspects of infertility as well as factors that have led to a global decline in sperm counts among men and the financial costs of treatment.

Dr. Nam said infertility is a sensitive topic for couples and families to talk about and there is less conversation about male infertility than female infertility. “I think the only way that we can be able to make headway, both in terms of protocol and policy outcomes, is to really start to raise awareness,” said Dr. Nam, who is doing a fellowship in clinical andrology at Northwestern University, in Chicago.

Dr. Nam said the collaborative environment of MOBYUS has enabled her to learn about different practice patterns across different institutions. “For someone like me just starting off my professional career in male infertility, an opportunity like this is incredibly exciting and makes me very hopeful about the kinds of collaboration and scientific discovery that we’re able to do together as a group,” she said.

Robert E. Brannigan, MD, vice chair of clinical urology at Northwestern University Feinberg School of Medicine, Chicago, said the consortium is drawing on the strength of many individual centers and allowing them to study critical issues in the field. The group’s outstanding clinicians and scientists “are looking to move the field forward, and I applaud them and I’m eager to watch things unfold,” said Dr. Brannigan, who is not a member of the group.

Dr. Brannigan noted that for a large percentage of patients, clinicians cannot identify the root cause of their impaired reproductive potential. Some people may have a recognizable decline in semen parameters over time without clear lifestyle issues or clear hormonal imbalances or anatomical problems. 

“And the question is, what’s causing that? Is there some as yet unrecognized environmental exposure? Is there some underlying genetic issue that’s predisposing to decline in semen parameters over time? We see this, and we don’t have answers,” Dr. Brannigan said. 

“This is where I think the potential power of a large group like MOBYUS comes into play,” he added. “When you’ve got large datasets and very granular information about your patients, sometimes that can provide the opportunity for insights that can then answer the question, ‘What is the root cause of my patient’s challenges?’ ”

Dr. Brannigan was part of a previous group, the Andrology Research Consortium, which collected data on patient history and treatment through a standardized questionnaire. The consortium was founded in 2013 by the Society for the Study of Male Reproduction, a specialty section of the American Urological Association, to obtain data on the demographics, clinical characteristics, and fertility histories and therapies of men referred for a male infertility investigation at clinics across North America. 

Clinicians analyzed data from the questionnaires, which a team in Toronto collected and stored, in a series of studies, including a comparison of fertility characteristics between men in the United States and Canada. Dr. Brannigan said MOBYUS is poised to produce a large dataset that can address retrospective questions and potentially prospectively collect data to answer prospective questions.
 

Clinical Implications

Dr. Lundy said between 100 and 200 practicing reproductive urologists across the country regularly communicate with each other. He first raised the idea of creating a consortium with friends and colleagues and then discussed it at scientific meetings. The network steadily gained traction and is continuing to add institutions. “There’s a great deal of excitement in our community about this,” Dr. Lundy said.

MOBYUS, which is IRB approved, has a database with data from more than 4000 patients. The consortium has not received any industry funding but plans to pursue grant applications in the future. 

The MOBYUS website includes a list of its member institutions and leading investigators and its three proof-of-principle manuscripts published to date. The team identifies new research projects at monthly virtual meetings.

Dr. Lundy said MOBYUS’ main goal is to identify a treatment that will change the avenue available for a couple to get pregnant. For example, he said, if a man has zero sperm in his semen, he often requires surgery to find and remove sperm from the testicle. If medications can produce low sperm counts, sperm found in the ejaculate can be frozen and surgery can be avoided. 

Dr. Lundy said MOBYUS’ two publications on medical therapies have changed clinical practice, as he and many others have begun to provide the treatments on more carefully selected patients with good outcomes. 

Dr. Nam said patients want to know what they can expect from therapies and these research findings will have “a lot of clinical implications” in counseling them. 

The MOBYUS team will be describing the consortium and its goals in an abstract presentation at the American Society for Reproductive Medicine Scientific Congress & Expo, to be held October 19-23 in Denver, Colorado, and in an oral presentation at the Sexual Medicine Society of North America’s annual fall scientific meeting, to be held October 17-20 in Scottsdale, Arizona.

The sources in this story reported no relevant financial conflicts of interest.
 

A version of this article first appeared on Medscape.com.

COPENHAGEN — Women of childbearing age with multiple sclerosis (MS) receive fewer highly effective medications than do men with similar levels of disability, even after accounting for treatment discontinuations during pregnancy and the postpartum period, new research suggested.

“We believe that pregnancy-related considerations probably still explain the major part of this gap,” said Antoine Gavoille, MD, University of Lyon, France, who presented the study at the 2024 ECTRIMS annual meeting.

This is likely due to “factors such as anticipation of pregnancy long before it occurs and fear of exposing women of childbearing age to certain treatments even in the absence of planned pregnancy,” he added.

Caution is warranted when medications are first marketed because there are no data on safety in pregnancy. However, in 2024, “this lesser treatment in women is unacceptable,” said Dr. Gavoille. “We now have several highly effective treatment options which are compatible with pregnancy,” he noted.

The researchers analyzed the French MS registry of 22,657 patients with relapsing MS (74.2% women) between 1997 and 2022 for treatment differences between women and their male counterparts. The results were adjusted for multiple factors including educational level, disease activity, disability levels, and discontinuation of drugs during pregnancy.

They found that over a median follow-up of 11.6 years, women had a significantly lower probability of receiving any disease-modifying treatment (odds ratio [OR], 0.92; 95% CI, 0.87-0.97).

In addition, women were even less likely to receive high-efficacy treatments such as natalizumab, anti-CD20 antibodies, or S1P modulators such as fingolimod (OR, 0.80; 95% CI, 0.74-0.86).

The difference in disease-modifying treatment usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused throughout their entire availability (OR, 0.87, 0.78, and 0.80, respectively).

Interferon and natalizumab were initially used less frequently in women, but the use of these medications equalized over time.

In contrast, glatiramer acetate and dimethyl fumarate were initially used equally between genders but eventually became more commonly prescribed to women (OR, 1.27 and 1.17, respectively).

The disparity in treatment emerged after 2 years of disease duration for disease-modifying treatments in general and as early as 1 year for highly effective treatments.

The gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia may persist regardless of a woman’s age.

“Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialize,” said the study’s lead investigator Sandra Vukusic, MD, Lyon University Hospital, France.

“The main impact of this therapeutic inertia in women is the less effective control of disease activity, leading to the accumulation of lesions and an increased risk of long-term disability. This represents a real loss of opportunity for women, especially in an era where disease-modifying treatments so effective when used early,” she added.

Dr. Gavoille said that recommendations in France allow the use of moderately active drugs, including interferon and glatiramer acetate, during pregnancy or in women planning a pregnancy. More recently there has been enough data to allow the use of natalizumab up until the second trimester.

In addition, although not in the guidelines, it is thought that the anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab, may be safe as they are very long acting. Women can be dosed before pregnancy and be covered for the whole pregnancy period without exposing the fetus to the drug, he explained.

“The message is that now we have both moderately and highly effective treatments that are compatible with a pregnancy plan,” Dr. Gavoille said.

First, clinicians have to select a level of treatment based on disease activity and then choose the best option, depending on the woman’s plans with respect to pregnancy.

Drugs that are contraindicated in pregnancy include teriflunomide and S1P modulators such as fingolimod, which have been shown to be harmful to the fetus.

“But they could still be used in women of childbearing years as long as they are not planning a pregnancy and understand the need for contraception,” Dr. Gavoille noted.

He believes both neurologists and patients are afraid of using drugs in pregnancy. “It is, of course, important to be cautious on this issue, but we should not let fear stop these women receiving the best treatments available.”

However, he added, clinical practice is changing, and confidence is gradually building around using highly effective treatments in women of childbearing age.

Dr. Gavoille also called for more research to collate data in pregnant women with MS who are exposed to various treatments, starting with case reports and then academic registries, which he described as “difficult but important work.”

Commenting on the study, Robert Hoepner, MD, University Hospital of Bern, Switzerland, agreed that this treatment disparity between men and women is “unacceptable.”

Dr. Hoepner noted that a recent study showed that women have different relapse symptoms than men, which may also affect treatment choice.

Dr. Gavoille responded that other research has shown that women are less likely to have treatment escalation post-relapse. “This could be because of a difference in symptoms. But this is something we haven’t looked at yet.” 

Also commenting on the research, Frauke Zipp, MD, University Medical Center Mainz in Germany, said it would be interesting to follow this cohort over the long term to see if the women do less well several years down the line.

The study authors and commentators reported no relevant disclosures.
 

A version of this article first appeared on Medscape.com.

COPENHAGEN — Women of childbearing age with multiple sclerosis (MS) receive fewer highly effective medications than do men with similar levels of disability, even after accounting for treatment discontinuations during pregnancy and the postpartum period, new research suggested.

“We believe that pregnancy-related considerations probably still explain the major part of this gap,” said Antoine Gavoille, MD, University of Lyon, France, who presented the study at the 2024 ECTRIMS annual meeting.

This is likely due to “factors such as anticipation of pregnancy long before it occurs and fear of exposing women of childbearing age to certain treatments even in the absence of planned pregnancy,” he added.

Caution is warranted when medications are first marketed because there are no data on safety in pregnancy. However, in 2024, “this lesser treatment in women is unacceptable,” said Dr. Gavoille. “We now have several highly effective treatment options which are compatible with pregnancy,” he noted.

The researchers analyzed the French MS registry of 22,657 patients with relapsing MS (74.2% women) between 1997 and 2022 for treatment differences between women and their male counterparts. The results were adjusted for multiple factors including educational level, disease activity, disability levels, and discontinuation of drugs during pregnancy.

They found that over a median follow-up of 11.6 years, women had a significantly lower probability of receiving any disease-modifying treatment (odds ratio [OR], 0.92; 95% CI, 0.87-0.97).

In addition, women were even less likely to receive high-efficacy treatments such as natalizumab, anti-CD20 antibodies, or S1P modulators such as fingolimod (OR, 0.80; 95% CI, 0.74-0.86).

The difference in disease-modifying treatment usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused throughout their entire availability (OR, 0.87, 0.78, and 0.80, respectively).

Interferon and natalizumab were initially used less frequently in women, but the use of these medications equalized over time.

In contrast, glatiramer acetate and dimethyl fumarate were initially used equally between genders but eventually became more commonly prescribed to women (OR, 1.27 and 1.17, respectively).

The disparity in treatment emerged after 2 years of disease duration for disease-modifying treatments in general and as early as 1 year for highly effective treatments.

The gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia may persist regardless of a woman’s age.

“Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialize,” said the study’s lead investigator Sandra Vukusic, MD, Lyon University Hospital, France.

“The main impact of this therapeutic inertia in women is the less effective control of disease activity, leading to the accumulation of lesions and an increased risk of long-term disability. This represents a real loss of opportunity for women, especially in an era where disease-modifying treatments so effective when used early,” she added.

Dr. Gavoille said that recommendations in France allow the use of moderately active drugs, including interferon and glatiramer acetate, during pregnancy or in women planning a pregnancy. More recently there has been enough data to allow the use of natalizumab up until the second trimester.

In addition, although not in the guidelines, it is thought that the anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab, may be safe as they are very long acting. Women can be dosed before pregnancy and be covered for the whole pregnancy period without exposing the fetus to the drug, he explained.

“The message is that now we have both moderately and highly effective treatments that are compatible with a pregnancy plan,” Dr. Gavoille said.

First, clinicians have to select a level of treatment based on disease activity and then choose the best option, depending on the woman’s plans with respect to pregnancy.

Drugs that are contraindicated in pregnancy include teriflunomide and S1P modulators such as fingolimod, which have been shown to be harmful to the fetus.

“But they could still be used in women of childbearing years as long as they are not planning a pregnancy and understand the need for contraception,” Dr. Gavoille noted.

He believes both neurologists and patients are afraid of using drugs in pregnancy. “It is, of course, important to be cautious on this issue, but we should not let fear stop these women receiving the best treatments available.”

However, he added, clinical practice is changing, and confidence is gradually building around using highly effective treatments in women of childbearing age.

Dr. Gavoille also called for more research to collate data in pregnant women with MS who are exposed to various treatments, starting with case reports and then academic registries, which he described as “difficult but important work.”

Commenting on the study, Robert Hoepner, MD, University Hospital of Bern, Switzerland, agreed that this treatment disparity between men and women is “unacceptable.”

Dr. Hoepner noted that a recent study showed that women have different relapse symptoms than men, which may also affect treatment choice.

Dr. Gavoille responded that other research has shown that women are less likely to have treatment escalation post-relapse. “This could be because of a difference in symptoms. But this is something we haven’t looked at yet.” 

Also commenting on the research, Frauke Zipp, MD, University Medical Center Mainz in Germany, said it would be interesting to follow this cohort over the long term to see if the women do less well several years down the line.

The study authors and commentators reported no relevant disclosures.
 

A version of this article first appeared on Medscape.com.

COPENHAGEN — Women of childbearing age with multiple sclerosis (MS) receive fewer highly effective medications than do men with similar levels of disability, even after accounting for treatment discontinuations during pregnancy and the postpartum period, new research suggested.

“We believe that pregnancy-related considerations probably still explain the major part of this gap,” said Antoine Gavoille, MD, University of Lyon, France, who presented the study at the 2024 ECTRIMS annual meeting.

This is likely due to “factors such as anticipation of pregnancy long before it occurs and fear of exposing women of childbearing age to certain treatments even in the absence of planned pregnancy,” he added.

Caution is warranted when medications are first marketed because there are no data on safety in pregnancy. However, in 2024, “this lesser treatment in women is unacceptable,” said Dr. Gavoille. “We now have several highly effective treatment options which are compatible with pregnancy,” he noted.

The researchers analyzed the French MS registry of 22,657 patients with relapsing MS (74.2% women) between 1997 and 2022 for treatment differences between women and their male counterparts. The results were adjusted for multiple factors including educational level, disease activity, disability levels, and discontinuation of drugs during pregnancy.

They found that over a median follow-up of 11.6 years, women had a significantly lower probability of receiving any disease-modifying treatment (odds ratio [OR], 0.92; 95% CI, 0.87-0.97).

In addition, women were even less likely to receive high-efficacy treatments such as natalizumab, anti-CD20 antibodies, or S1P modulators such as fingolimod (OR, 0.80; 95% CI, 0.74-0.86).

The difference in disease-modifying treatment usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused throughout their entire availability (OR, 0.87, 0.78, and 0.80, respectively).

Interferon and natalizumab were initially used less frequently in women, but the use of these medications equalized over time.

In contrast, glatiramer acetate and dimethyl fumarate were initially used equally between genders but eventually became more commonly prescribed to women (OR, 1.27 and 1.17, respectively).

The disparity in treatment emerged after 2 years of disease duration for disease-modifying treatments in general and as early as 1 year for highly effective treatments.

The gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia may persist regardless of a woman’s age.

“Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialize,” said the study’s lead investigator Sandra Vukusic, MD, Lyon University Hospital, France.

“The main impact of this therapeutic inertia in women is the less effective control of disease activity, leading to the accumulation of lesions and an increased risk of long-term disability. This represents a real loss of opportunity for women, especially in an era where disease-modifying treatments so effective when used early,” she added.

Dr. Gavoille said that recommendations in France allow the use of moderately active drugs, including interferon and glatiramer acetate, during pregnancy or in women planning a pregnancy. More recently there has been enough data to allow the use of natalizumab up until the second trimester.

In addition, although not in the guidelines, it is thought that the anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab, may be safe as they are very long acting. Women can be dosed before pregnancy and be covered for the whole pregnancy period without exposing the fetus to the drug, he explained.

“The message is that now we have both moderately and highly effective treatments that are compatible with a pregnancy plan,” Dr. Gavoille said.

First, clinicians have to select a level of treatment based on disease activity and then choose the best option, depending on the woman’s plans with respect to pregnancy.

Drugs that are contraindicated in pregnancy include teriflunomide and S1P modulators such as fingolimod, which have been shown to be harmful to the fetus.

“But they could still be used in women of childbearing years as long as they are not planning a pregnancy and understand the need for contraception,” Dr. Gavoille noted.

He believes both neurologists and patients are afraid of using drugs in pregnancy. “It is, of course, important to be cautious on this issue, but we should not let fear stop these women receiving the best treatments available.”

However, he added, clinical practice is changing, and confidence is gradually building around using highly effective treatments in women of childbearing age.

Dr. Gavoille also called for more research to collate data in pregnant women with MS who are exposed to various treatments, starting with case reports and then academic registries, which he described as “difficult but important work.”

Commenting on the study, Robert Hoepner, MD, University Hospital of Bern, Switzerland, agreed that this treatment disparity between men and women is “unacceptable.”

Dr. Hoepner noted that a recent study showed that women have different relapse symptoms than men, which may also affect treatment choice.

Dr. Gavoille responded that other research has shown that women are less likely to have treatment escalation post-relapse. “This could be because of a difference in symptoms. But this is something we haven’t looked at yet.” 

Also commenting on the research, Frauke Zipp, MD, University Medical Center Mainz in Germany, said it would be interesting to follow this cohort over the long term to see if the women do less well several years down the line.

The study authors and commentators reported no relevant disclosures.
 

A version of this article first appeared on Medscape.com.

MILAN — Antidepressants escitalopram and duloxetine have been shown to improve verbal memory in moderate to severe depression, a clinical effect linked to changes in serotonin 4 (5-HT4) receptor levels in the brain, as shown on PET.

These findings suggested there is a role for specifically targeting the 5-HT4 receptor to improve verbal memory in depression, said investigator Vibeke H. Dam, PhD, from Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

“Verbal memory is often impaired in depression, and this has a lot of impact on patients’ ability to work and have a normal life. That’s why we’re so excited about this receptor in particular,” Dr. Dam said.

“If we can find a way to activate it more directly, we’re thinking this could be a way to treat this memory symptom that a lot of patients have and that currently we don’t really have a treatment for,” she added.

The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress and recently published in Biological Psychiatry .
 

Largest Trial of Its Kind

The study is the largest single-site PET trial investigating serotonergic neurotransmission in major depressive disorder over the course of antidepressant treatment to date. It included 90 patients with moderate to severe depression who underwent baseline cognitive tests and brain scans to measure 5-HT4 receptor levels before starting their treatment with the selective serotonin reuptake inhibitor escitalopram.

Patients who showed no improvement in depressive symptoms after 4 weeks (n = 14), as assessed by the Hamilton Depression Rating Scale 6 (HAMD6), were switched to the serotonin-norepinephrine reuptake inhibitor duloxetine.

Both escitalopram and duloxetine inhibit the reuptake of 5-HT4, enhancing neurotransmitter activity; escitalopram primarily increases serotonin levels, while duloxetine increases both serotonin and norepinephrine levels.

The primary cognitive outcome measure was change in the Verbal Affective Memory Task 26. Secondary cognitive outcomes were change in working memory, reaction time, emotion recognition bias, and negative social emotion.

After 8 weeks of treatment, a subset of 40 patients repeated PET scans, and at 12 weeks, all patients repeated cognitive testing.

Matching neuroimaging and cognitive data were available for 88 patients at baseline and for 39 patients with rescan.

As expected, the study showed that antidepressant treatment resulted in the downregulation of 5-HT4 receptor levels. “One hypothesis is that if we increase the availability of serotonin [with treatment], downregulation of the receptors might be a response,” said Dr. Dam.

“What was interesting was that this was the effect across all patients, whether they [clinically] responded or not. So we see the medication does what it’s supposed to do in the brain.” But, she said, there was no association between 5-HT4 receptor levels and HAMD6 scores.
 

Gains in Verbal Memory

Although the downregulation of 5-HT4 did not correlate with somatic or mood symptoms, it did correlate with cognitive symptoms.

Interestingly, while most patients showed improvement in depressive symptoms — many reaching remission or recovery — they also experienced gains in verbal memory. However, these improvements were not correlated. It was possible for one to improve more than the other, with no apparent link between the two, said Dr. Dam.

“What was linked was how the brain responded to the medication for this particular receptor. So even though there is this downregulation of the receptor, there’s still a lot of activation of it, and our thinking is that it’s activation of the receptor that is the important bit.”

Work by other groups has shown that another medication, prucalopride, which is used to treat gastroparesis, can more directly activate the 5-HT4 receptor, and that the treatment of healthy volunteers with this medication can boost memory and learning, said Dr. Dam.

“We could repurpose this drug, and we’re currently looking for funding to test this in a wide variety of different groups such as concussion, diabetes, and depression.”

The study’s coinvestigator, Vibe G. Frokjaer, MD, said more research is required to understand the potential implications of the findings.

“Poor cognitive function is very hard to treat efficiently and may require extra treatment. This work points to the possibility of stimulating this specific receptor so that we can treat cognitive problems, even aside from whether or not the patient has overcome the core symptoms of depression,” she said in a release.

Commenting on the research, Philip Cowen, MD, professor of psychopharmacology at the University of Oxford, England, said in a release that in light of “recent controversies about the role of brain serotonin in clinical depression, it is noteworthy that the PET studies of the Copenhagen Group provide unequivocal evidence that brain 5-HT4 receptors are decreased in unmedicated depressed patients.

“Their work also demonstrates the intimate role of brain 5-HT4 receptors in cognitive function,” he added. “This confirms recent work from Oxford, showing that the 5-HT4 receptor stimulant, prucalopride — a drug licensed for the treatment of constipation — improves memory in both healthy participants and people at risk of depression,” he added.

The study was funded by the Innovation Fund Denmark, Research Fund of the Mental Health Services – Capital Region of Denmark, Independent Research Fund Denmark, Global Justice Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savværksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation, and H. Lundbeck A/S.

Dr. Dam reported serving as a speaker for H. Lundbeck. Frokjaer reported serving as a consultant for Sage Therapeutics and lecturer for H. Lundbeck, Janssen-Cilag, and Gedeon Richter. Study investigator Martin B. Jørgensen has given talks sponsored by Boehringer Ingelheim and Lundbeck Pharma. All other investigators reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

MILAN — Antidepressants escitalopram and duloxetine have been shown to improve verbal memory in moderate to severe depression, a clinical effect linked to changes in serotonin 4 (5-HT4) receptor levels in the brain, as shown on PET.

These findings suggested there is a role for specifically targeting the 5-HT4 receptor to improve verbal memory in depression, said investigator Vibeke H. Dam, PhD, from Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

“Verbal memory is often impaired in depression, and this has a lot of impact on patients’ ability to work and have a normal life. That’s why we’re so excited about this receptor in particular,” Dr. Dam said.

“If we can find a way to activate it more directly, we’re thinking this could be a way to treat this memory symptom that a lot of patients have and that currently we don’t really have a treatment for,” she added.

The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress and recently published in Biological Psychiatry .
 

Largest Trial of Its Kind

The study is the largest single-site PET trial investigating serotonergic neurotransmission in major depressive disorder over the course of antidepressant treatment to date. It included 90 patients with moderate to severe depression who underwent baseline cognitive tests and brain scans to measure 5-HT4 receptor levels before starting their treatment with the selective serotonin reuptake inhibitor escitalopram.

Patients who showed no improvement in depressive symptoms after 4 weeks (n = 14), as assessed by the Hamilton Depression Rating Scale 6 (HAMD6), were switched to the serotonin-norepinephrine reuptake inhibitor duloxetine.

Both escitalopram and duloxetine inhibit the reuptake of 5-HT4, enhancing neurotransmitter activity; escitalopram primarily increases serotonin levels, while duloxetine increases both serotonin and norepinephrine levels.

The primary cognitive outcome measure was change in the Verbal Affective Memory Task 26. Secondary cognitive outcomes were change in working memory, reaction time, emotion recognition bias, and negative social emotion.

After 8 weeks of treatment, a subset of 40 patients repeated PET scans, and at 12 weeks, all patients repeated cognitive testing.

Matching neuroimaging and cognitive data were available for 88 patients at baseline and for 39 patients with rescan.

As expected, the study showed that antidepressant treatment resulted in the downregulation of 5-HT4 receptor levels. “One hypothesis is that if we increase the availability of serotonin [with treatment], downregulation of the receptors might be a response,” said Dr. Dam.

“What was interesting was that this was the effect across all patients, whether they [clinically] responded or not. So we see the medication does what it’s supposed to do in the brain.” But, she said, there was no association between 5-HT4 receptor levels and HAMD6 scores.
 

Gains in Verbal Memory

Although the downregulation of 5-HT4 did not correlate with somatic or mood symptoms, it did correlate with cognitive symptoms.

Interestingly, while most patients showed improvement in depressive symptoms — many reaching remission or recovery — they also experienced gains in verbal memory. However, these improvements were not correlated. It was possible for one to improve more than the other, with no apparent link between the two, said Dr. Dam.

“What was linked was how the brain responded to the medication for this particular receptor. So even though there is this downregulation of the receptor, there’s still a lot of activation of it, and our thinking is that it’s activation of the receptor that is the important bit.”

Work by other groups has shown that another medication, prucalopride, which is used to treat gastroparesis, can more directly activate the 5-HT4 receptor, and that the treatment of healthy volunteers with this medication can boost memory and learning, said Dr. Dam.

“We could repurpose this drug, and we’re currently looking for funding to test this in a wide variety of different groups such as concussion, diabetes, and depression.”

The study’s coinvestigator, Vibe G. Frokjaer, MD, said more research is required to understand the potential implications of the findings.

“Poor cognitive function is very hard to treat efficiently and may require extra treatment. This work points to the possibility of stimulating this specific receptor so that we can treat cognitive problems, even aside from whether or not the patient has overcome the core symptoms of depression,” she said in a release.

Commenting on the research, Philip Cowen, MD, professor of psychopharmacology at the University of Oxford, England, said in a release that in light of “recent controversies about the role of brain serotonin in clinical depression, it is noteworthy that the PET studies of the Copenhagen Group provide unequivocal evidence that brain 5-HT4 receptors are decreased in unmedicated depressed patients.

“Their work also demonstrates the intimate role of brain 5-HT4 receptors in cognitive function,” he added. “This confirms recent work from Oxford, showing that the 5-HT4 receptor stimulant, prucalopride — a drug licensed for the treatment of constipation — improves memory in both healthy participants and people at risk of depression,” he added.

The study was funded by the Innovation Fund Denmark, Research Fund of the Mental Health Services – Capital Region of Denmark, Independent Research Fund Denmark, Global Justice Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savværksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation, and H. Lundbeck A/S.

Dr. Dam reported serving as a speaker for H. Lundbeck. Frokjaer reported serving as a consultant for Sage Therapeutics and lecturer for H. Lundbeck, Janssen-Cilag, and Gedeon Richter. Study investigator Martin B. Jørgensen has given talks sponsored by Boehringer Ingelheim and Lundbeck Pharma. All other investigators reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

MILAN — Antidepressants escitalopram and duloxetine have been shown to improve verbal memory in moderate to severe depression, a clinical effect linked to changes in serotonin 4 (5-HT4) receptor levels in the brain, as shown on PET.

These findings suggested there is a role for specifically targeting the 5-HT4 receptor to improve verbal memory in depression, said investigator Vibeke H. Dam, PhD, from Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

“Verbal memory is often impaired in depression, and this has a lot of impact on patients’ ability to work and have a normal life. That’s why we’re so excited about this receptor in particular,” Dr. Dam said.

“If we can find a way to activate it more directly, we’re thinking this could be a way to treat this memory symptom that a lot of patients have and that currently we don’t really have a treatment for,” she added.

The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress and recently published in Biological Psychiatry .
 

Largest Trial of Its Kind

The study is the largest single-site PET trial investigating serotonergic neurotransmission in major depressive disorder over the course of antidepressant treatment to date. It included 90 patients with moderate to severe depression who underwent baseline cognitive tests and brain scans to measure 5-HT4 receptor levels before starting their treatment with the selective serotonin reuptake inhibitor escitalopram.

Patients who showed no improvement in depressive symptoms after 4 weeks (n = 14), as assessed by the Hamilton Depression Rating Scale 6 (HAMD6), were switched to the serotonin-norepinephrine reuptake inhibitor duloxetine.

Both escitalopram and duloxetine inhibit the reuptake of 5-HT4, enhancing neurotransmitter activity; escitalopram primarily increases serotonin levels, while duloxetine increases both serotonin and norepinephrine levels.

The primary cognitive outcome measure was change in the Verbal Affective Memory Task 26. Secondary cognitive outcomes were change in working memory, reaction time, emotion recognition bias, and negative social emotion.

After 8 weeks of treatment, a subset of 40 patients repeated PET scans, and at 12 weeks, all patients repeated cognitive testing.

Matching neuroimaging and cognitive data were available for 88 patients at baseline and for 39 patients with rescan.

As expected, the study showed that antidepressant treatment resulted in the downregulation of 5-HT4 receptor levels. “One hypothesis is that if we increase the availability of serotonin [with treatment], downregulation of the receptors might be a response,” said Dr. Dam.

“What was interesting was that this was the effect across all patients, whether they [clinically] responded or not. So we see the medication does what it’s supposed to do in the brain.” But, she said, there was no association between 5-HT4 receptor levels and HAMD6 scores.
 

Gains in Verbal Memory

Although the downregulation of 5-HT4 did not correlate with somatic or mood symptoms, it did correlate with cognitive symptoms.

Interestingly, while most patients showed improvement in depressive symptoms — many reaching remission or recovery — they also experienced gains in verbal memory. However, these improvements were not correlated. It was possible for one to improve more than the other, with no apparent link between the two, said Dr. Dam.

“What was linked was how the brain responded to the medication for this particular receptor. So even though there is this downregulation of the receptor, there’s still a lot of activation of it, and our thinking is that it’s activation of the receptor that is the important bit.”

Work by other groups has shown that another medication, prucalopride, which is used to treat gastroparesis, can more directly activate the 5-HT4 receptor, and that the treatment of healthy volunteers with this medication can boost memory and learning, said Dr. Dam.

“We could repurpose this drug, and we’re currently looking for funding to test this in a wide variety of different groups such as concussion, diabetes, and depression.”

The study’s coinvestigator, Vibe G. Frokjaer, MD, said more research is required to understand the potential implications of the findings.

“Poor cognitive function is very hard to treat efficiently and may require extra treatment. This work points to the possibility of stimulating this specific receptor so that we can treat cognitive problems, even aside from whether or not the patient has overcome the core symptoms of depression,” she said in a release.

Commenting on the research, Philip Cowen, MD, professor of psychopharmacology at the University of Oxford, England, said in a release that in light of “recent controversies about the role of brain serotonin in clinical depression, it is noteworthy that the PET studies of the Copenhagen Group provide unequivocal evidence that brain 5-HT4 receptors are decreased in unmedicated depressed patients.

“Their work also demonstrates the intimate role of brain 5-HT4 receptors in cognitive function,” he added. “This confirms recent work from Oxford, showing that the 5-HT4 receptor stimulant, prucalopride — a drug licensed for the treatment of constipation — improves memory in both healthy participants and people at risk of depression,” he added.

The study was funded by the Innovation Fund Denmark, Research Fund of the Mental Health Services – Capital Region of Denmark, Independent Research Fund Denmark, Global Justice Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savværksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation, and H. Lundbeck A/S.

Dr. Dam reported serving as a speaker for H. Lundbeck. Frokjaer reported serving as a consultant for Sage Therapeutics and lecturer for H. Lundbeck, Janssen-Cilag, and Gedeon Richter. Study investigator Martin B. Jørgensen has given talks sponsored by Boehringer Ingelheim and Lundbeck Pharma. All other investigators reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

MILAN, ITALY — Pregnant women with heightened amygdala activity have a reduced capacity to regulate emotions and report more symptoms of depression than those with lower activity in this brain region, a new imaging study suggested.

If validated, these findings could pave the way for identifying women at higher risk for postpartum depression, said lead researcher Franziska Weinmar, MSc, from the University of Tübingen in Germany.

The study was presented at the 37th European College of Neuropsychopharmacology Congress.
 

Differences in Brain Activity

During pregnancy and the peripartum period, rising hormone levels create a “psychoneuroendocrinological window of vulnerability” for mental health in which 80% of women can develop transitory “baby blues,” and about one in seven develop more serious postpartum depression, Ms. Weinmar told this news organization.

The study included 47 women — 15 pregnant women and 32 nonpregnant controls. The nonpregnant women had normal menstrual cycles; 16 were in the early follicular phase with low estradiol levels (231.7 pmol/L), and 16 had high estradiol levels (516.6 pmol/L) after administration of estradiol.

To examine brain activity, participants were asked to view negative emotional images while undergoing functional MRI. They were then asked to use cognitive reappraisal to regulate their emotional response to the images.

The findings showed that both pregnant and nonpregnant women were equally successful at emotional regulation, but this process involved different brain activity in pregnant vs their nonpregnant counterpart.

All women had increased left middle frontal gyrus activity when regulating their emotions, but there was a difference in the amygdala between the pregnancy group and controls, Ms. Weinmar noted.

This suggests that pregnant women may have to exert more neural effort in emotional regulation, she said. “And pregnant women with higher amygdala activity were less able to regulate their emotions successfully compared to those with less amygdala activity.”

Linear regression analyses were performed to assess the relation of brain activity during down-regulation, regulation success, and self-reported depression scores, and this showed that higher amygdala activity was also associated with higher depression scores.

“We need to be cautious in interpreting this,” said Ms. Weinmar. “This is a small sample, and we are the first to undertake this work.”

Nonetheless, she said that if the findings are confirmed by larger studies, pregnant women could be assessed “in the waiting room” using existing questionnaires that evaluate emotional regulation.

If a woman has difficulties with emotion regulation, “there are adaptive strategies, like cognitive reappraisal that a counseling psychotherapist can help with,” said Ms. Weinmar.

“I could also imagine group sessions, for example, or online courses,” she said, adding that obstetricians could also be trained to identify these women.

Commenting on the findings in a press release, Susana Carmona, PhD, from Gregorio Marañón Hospital in Madrid, Spain, said research like this is crucial for gaining insight into one of the most intense physiological processes a human can undergo: pregnancy. It’s remarkable how much remains unknown.

“Recently, the FDA [Food and Drug Administration] approved the first treatment for postpartum depression. However, we still have a long way to go in characterizing what happens in the brain during pregnancy, identifying biomarkers that can indicate the risk of developing perinatal mental disorders, and designing strategies to prevent mother and infant suffering during the delicate and critical peripartum period,” Dr. Carmona added.

The study was supported by the Center for Integrative Neuroscience in Tübingen, Germany, and the International Research Training Group “Women’s Mental Health Across the Reproductive Years” (IRTG 2804). Ms. Weinmar and Dr. Carmona reported no relevant disclosures.

A version of this article appeared on Medscape.com.

MILAN, ITALY — Pregnant women with heightened amygdala activity have a reduced capacity to regulate emotions and report more symptoms of depression than those with lower activity in this brain region, a new imaging study suggested.

If validated, these findings could pave the way for identifying women at higher risk for postpartum depression, said lead researcher Franziska Weinmar, MSc, from the University of Tübingen in Germany.

The study was presented at the 37th European College of Neuropsychopharmacology Congress.
 

Differences in Brain Activity

During pregnancy and the peripartum period, rising hormone levels create a “psychoneuroendocrinological window of vulnerability” for mental health in which 80% of women can develop transitory “baby blues,” and about one in seven develop more serious postpartum depression, Ms. Weinmar told this news organization.

The study included 47 women — 15 pregnant women and 32 nonpregnant controls. The nonpregnant women had normal menstrual cycles; 16 were in the early follicular phase with low estradiol levels (231.7 pmol/L), and 16 had high estradiol levels (516.6 pmol/L) after administration of estradiol.

To examine brain activity, participants were asked to view negative emotional images while undergoing functional MRI. They were then asked to use cognitive reappraisal to regulate their emotional response to the images.

The findings showed that both pregnant and nonpregnant women were equally successful at emotional regulation, but this process involved different brain activity in pregnant vs their nonpregnant counterpart.

All women had increased left middle frontal gyrus activity when regulating their emotions, but there was a difference in the amygdala between the pregnancy group and controls, Ms. Weinmar noted.

This suggests that pregnant women may have to exert more neural effort in emotional regulation, she said. “And pregnant women with higher amygdala activity were less able to regulate their emotions successfully compared to those with less amygdala activity.”

Linear regression analyses were performed to assess the relation of brain activity during down-regulation, regulation success, and self-reported depression scores, and this showed that higher amygdala activity was also associated with higher depression scores.

“We need to be cautious in interpreting this,” said Ms. Weinmar. “This is a small sample, and we are the first to undertake this work.”

Nonetheless, she said that if the findings are confirmed by larger studies, pregnant women could be assessed “in the waiting room” using existing questionnaires that evaluate emotional regulation.

If a woman has difficulties with emotion regulation, “there are adaptive strategies, like cognitive reappraisal that a counseling psychotherapist can help with,” said Ms. Weinmar.

“I could also imagine group sessions, for example, or online courses,” she said, adding that obstetricians could also be trained to identify these women.

Commenting on the findings in a press release, Susana Carmona, PhD, from Gregorio Marañón Hospital in Madrid, Spain, said research like this is crucial for gaining insight into one of the most intense physiological processes a human can undergo: pregnancy. It’s remarkable how much remains unknown.

“Recently, the FDA [Food and Drug Administration] approved the first treatment for postpartum depression. However, we still have a long way to go in characterizing what happens in the brain during pregnancy, identifying biomarkers that can indicate the risk of developing perinatal mental disorders, and designing strategies to prevent mother and infant suffering during the delicate and critical peripartum period,” Dr. Carmona added.

The study was supported by the Center for Integrative Neuroscience in Tübingen, Germany, and the International Research Training Group “Women’s Mental Health Across the Reproductive Years” (IRTG 2804). Ms. Weinmar and Dr. Carmona reported no relevant disclosures.

A version of this article appeared on Medscape.com.

MILAN, ITALY — Pregnant women with heightened amygdala activity have a reduced capacity to regulate emotions and report more symptoms of depression than those with lower activity in this brain region, a new imaging study suggested.

If validated, these findings could pave the way for identifying women at higher risk for postpartum depression, said lead researcher Franziska Weinmar, MSc, from the University of Tübingen in Germany.

The study was presented at the 37th European College of Neuropsychopharmacology Congress.
 

Differences in Brain Activity

During pregnancy and the peripartum period, rising hormone levels create a “psychoneuroendocrinological window of vulnerability” for mental health in which 80% of women can develop transitory “baby blues,” and about one in seven develop more serious postpartum depression, Ms. Weinmar told this news organization.

The study included 47 women — 15 pregnant women and 32 nonpregnant controls. The nonpregnant women had normal menstrual cycles; 16 were in the early follicular phase with low estradiol levels (231.7 pmol/L), and 16 had high estradiol levels (516.6 pmol/L) after administration of estradiol.

To examine brain activity, participants were asked to view negative emotional images while undergoing functional MRI. They were then asked to use cognitive reappraisal to regulate their emotional response to the images.

The findings showed that both pregnant and nonpregnant women were equally successful at emotional regulation, but this process involved different brain activity in pregnant vs their nonpregnant counterpart.

All women had increased left middle frontal gyrus activity when regulating their emotions, but there was a difference in the amygdala between the pregnancy group and controls, Ms. Weinmar noted.

This suggests that pregnant women may have to exert more neural effort in emotional regulation, she said. “And pregnant women with higher amygdala activity were less able to regulate their emotions successfully compared to those with less amygdala activity.”

Linear regression analyses were performed to assess the relation of brain activity during down-regulation, regulation success, and self-reported depression scores, and this showed that higher amygdala activity was also associated with higher depression scores.

“We need to be cautious in interpreting this,” said Ms. Weinmar. “This is a small sample, and we are the first to undertake this work.”

Nonetheless, she said that if the findings are confirmed by larger studies, pregnant women could be assessed “in the waiting room” using existing questionnaires that evaluate emotional regulation.

If a woman has difficulties with emotion regulation, “there are adaptive strategies, like cognitive reappraisal that a counseling psychotherapist can help with,” said Ms. Weinmar.

“I could also imagine group sessions, for example, or online courses,” she said, adding that obstetricians could also be trained to identify these women.

Commenting on the findings in a press release, Susana Carmona, PhD, from Gregorio Marañón Hospital in Madrid, Spain, said research like this is crucial for gaining insight into one of the most intense physiological processes a human can undergo: pregnancy. It’s remarkable how much remains unknown.

“Recently, the FDA [Food and Drug Administration] approved the first treatment for postpartum depression. However, we still have a long way to go in characterizing what happens in the brain during pregnancy, identifying biomarkers that can indicate the risk of developing perinatal mental disorders, and designing strategies to prevent mother and infant suffering during the delicate and critical peripartum period,” Dr. Carmona added.

The study was supported by the Center for Integrative Neuroscience in Tübingen, Germany, and the International Research Training Group “Women’s Mental Health Across the Reproductive Years” (IRTG 2804). Ms. Weinmar and Dr. Carmona reported no relevant disclosures.

A version of this article appeared on Medscape.com.